|
1
|
Richter EA, Bilan PJ, Klip A. A comprehensive view of muscle glucose uptake: regulation by insulin, contractile activity, and exercise. Physiol Rev 2025; 105:1867-1945. [PMID: 40173020 DOI: 10.1152/physrev.00033.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Revised: 11/07/2024] [Accepted: 03/08/2025] [Indexed: 04/04/2025] Open
Abstract
Skeletal muscle is the main site of glucose deposition in the body during meals and the major glucose utilizer during physical activity. Although in both instances the supply of glucose from the circulation to the muscle is of paramount importance, in most conditions the rate-limiting step in glucose uptake, storage, and utilization is the transport of glucose across the muscle cell membrane. This step is dependent upon the translocation of the insulin- and contraction-responsive glucose transporter GLUT4 from intracellular storage sites to the sarcolemma and T tubules. Here, we first analyze how glucose can traverse the capillary wall into the muscle interstitial space. We then review the molecular processes that regulate GLUT4 translocation in response to insulin and muscle contractions and the methodologies utilized to unravel them. We further discuss how physical activity and inactivity, respectively, lead to increased and decreased insulin action in muscle and touch upon sex differences in glucose metabolism. Although many key processes regulating glucose uptake in muscle are known, the advent of newer and bioinformatics tools has revealed further molecular signaling processes reaching a staggering level of complexity. Much of this molecular mapping has emerged from cellular and animal studies and more recently from application of a variety of -omics in human tissues. In the future, it will be imperative to validate the translatability of results drawn from experimental systems to human physiology.
Collapse
Affiliation(s)
- Erik A Richter
- Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
| | - Philip J Bilan
- Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Amira Klip
- Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada
| |
Collapse
|
|
2
|
O'Reilly CL, Uranga S, Fluckey JD. Culprits or consequences: Understanding the metabolic dysregulation of muscle in diabetes. World J Biol Chem 2021; 12:70-86. [PMID: 34630911 PMCID: PMC8473417 DOI: 10.4331/wjbc.v12.i5.70] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 06/21/2021] [Accepted: 08/03/2021] [Indexed: 02/06/2023] Open
Abstract
The prevalence of type 2 diabetes (T2D) continues to rise despite the amount of research dedicated to finding the culprits of this debilitating disease. Skeletal muscle is arguably the most important contributor to glucose disposal making it a clear target in insulin resistance and T2D research. Within skeletal muscle there is a clear link to metabolic dysregulation during the progression of T2D but the determination of culprits vs consequences of the disease has been elusive. Emerging evidence in skeletal muscle implicates influential cross talk between a key anabolic regulatory protein, the mammalian target of rapamycin (mTOR) and its associated complexes (mTORC1 and mTORC2), and the well-described canonical signaling for insulin-stimulated glucose uptake. This new understanding of cellular signaling crosstalk has blurred the lines of what is a culprit and what is a consequence with regard to insulin resistance. Here, we briefly review the most recent understanding of insulin signaling in skeletal muscle, and how anabolic responses favoring anabolism directly impact cellular glucose disposal. This review highlights key cross-over interactions between protein and glucose regulatory pathways and the implications this may have for the design of new therapeutic targets for the control of glucoregulatory function in skeletal muscle.
Collapse
Affiliation(s)
| | - Selina Uranga
- Health and Kinesiology, Texas A&M University, TX 77843, United States
| | - James D Fluckey
- Health and Kinesiology, Texas A&M University, TX 77843, United States
| |
Collapse
|
|
3
|
Nozato Y, Takami Y, Yamamoto K, Nagasawa M, Nozato S, Imaizumi Y, Takeshita H, Wang C, Ito Y, Takeda S, Takeya Y, Sugimoto K, Nakagami H, Hanayama R, Rakugi H. Novel properties of myoferlin in glucose metabolism via pathways involving modulation of adipose functions. FASEB J 2020; 34:2792-2811. [PMID: 31912559 DOI: 10.1096/fj.201901539rr] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Revised: 12/05/2019] [Accepted: 12/09/2019] [Indexed: 11/11/2022]
Abstract
While adipose tissue is required to maintain glucose metabolism, excessive calorie intake induces obesity via mechanisms including accelerated proliferation and differentiation of preadipocytes, leading to insulin resistance. Here, we investigated the role of myoferlin (MYOF), a ferlin family protein, in regulating glucose metabolism by mainly focusing on its unknown role in adipose tissue. Whereas young MYOF knockout (KO) mice on a normal diet showed aggravated glucose tolerance and insulin sensitivity, those on a high-fat diet (HFD) showed preserved glucose tolerance with an attenuated gain of body weight, reduced visceral fat deposits, and less severe fatty liver. The Adipose MYOF expression was reduced by aging but was restored by an HFD along with the retained expression of NFAT transcription factors. Loss-of-function of MYOF in preadipocytes suppressed proliferation and differentiation into mature adipocytes along with the decreased expression of genes involved in adipogenesis. The MYOF expression in preadipocytes was reduced with differentiation. Attenuated obesity in MYOF KO mice on an HFD was also accompanied with increased oxygen consumption by an unidentified mechanism and with reduced adipose inflammation due to less inflammatory macrophages. These insights suggest that the multifunctional roles of MYOF involve the regulation of preadipocyte function and affect glucose metabolism bidirectionally depending on consumed calories.
Collapse
Affiliation(s)
- Yoichi Nozato
- Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Suita, Japan
| | - Yoichi Takami
- Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Suita, Japan
| | - Koichi Yamamoto
- Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Suita, Japan
| | - Motonori Nagasawa
- Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Suita, Japan
| | - Satoko Nozato
- Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Suita, Japan
| | - Yuki Imaizumi
- Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Suita, Japan
| | - Hikari Takeshita
- Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Suita, Japan
| | - Cheng Wang
- Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Suita, Japan
| | - Yuki Ito
- Department of Clinical Gene Therapy, Osaka University Graduate School of Medicine, Suita, Japan
| | - Shuko Takeda
- Department of Clinical Gene Therapy, Osaka University Graduate School of Medicine, Suita, Japan
| | - Yasushi Takeya
- Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Suita, Japan
| | - Ken Sugimoto
- Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Suita, Japan
| | - Hironori Nakagami
- Department of Health Development and Medicine, Osaka University Graduate School of Medicine, Suita, Japan
| | - Rikinari Hanayama
- Department of Immunology, Graduate School of Medicine & WPI Nano Life Science Institute (NanoLSI), Kanazawa University, Kanazawa, Japan
| | - Hiromi Rakugi
- Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Suita, Japan
| |
Collapse
|
|
4
|
Welch KC, Myrka AM, Ali RS, Dick MF. The Metabolic Flexibility of Hovering Vertebrate Nectarivores. Physiology (Bethesda) 2018; 33:127-137. [DOI: 10.1152/physiol.00001.2018] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Foraging hummingbirds and nectar bats oxidize both glucose and fructose from nectar at exceptionally high rates. Rapid sugar flux is made possible by adaptations to digestive, cardiovascular, and metabolic physiology affecting shared and distinct pathways for the processing of each sugar. Still, how these animals partition and regulate the metabolism of each sugar and whether this occurs differently between hummingbirds and bats remain unclear.
Collapse
Affiliation(s)
- Kenneth C. Welch
- Department of Biological Sciences, University of Toronto Scarborough, Toronto, Ontario, Canada
- Department of Cell & Systems Biology, University of Toronto, Toronto, Ontario, Canada
- Center for the Neurobiology of Stress, University of Toronto Scarborough, Toronto, Ontario, Canada
| | - Alexander M. Myrka
- Department of Biological Sciences, University of Toronto Scarborough, Toronto, Ontario, Canada
- Department of Cell & Systems Biology, University of Toronto, Toronto, Ontario, Canada
| | - Raafay Syed Ali
- Department of Biological Sciences, University of Toronto Scarborough, Toronto, Ontario, Canada
- Department of Cell & Systems Biology, University of Toronto, Toronto, Ontario, Canada
| | - Morag F. Dick
- Department of Biological Sciences, University of Toronto Scarborough, Toronto, Ontario, Canada
- Department of Cell & Systems Biology, University of Toronto, Toronto, Ontario, Canada
| |
Collapse
|
|
5
|
Wasserman DH, Fueger P, Ploug T, Vinten J. Point: Counterpoint Glucose Phosphorylation is/ is not a Significant Barrier to Muscle Glucose Uptake By the Working Muscle. J Appl Physiol (1985) 2017:8172006. [PMID: 29357522 DOI: 10.1152/japplphysiol.00817.2006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
|
|
6
|
McGarrah RW, Slentz CA, Kraus WE. The Effect of Vigorous- Versus Moderate-Intensity Aerobic Exercise on Insulin Action. Curr Cardiol Rep 2017; 18:117. [PMID: 27796854 DOI: 10.1007/s11886-016-0797-7] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Due to the beneficial effects on a wide range of modern medical conditions, most professional societies recommend regular aerobic exercise as part of a healthy lifestyle. Many of the exercise-related health benefits exhibit a dose-response relationship: Up to a point, more exercise is more beneficial. However, recent studies have suggested that different exercise intensities may provide distinct health benefits, independent of energy expenditure (i.e., exercise dose). One of these benefits, primarily mediated by the skeletal muscle, is exercise-related changes in insulin action and glucose homeostasis. Glucose uptake in the exercising muscle occurs through insulin-independent mechanisms whose downstream signaling events ultimately converge with insulin-signaling pathways, a fact that may explain why exercise and insulin have additive effect on skeletal muscle glucose uptake. Although the existing evidence is somewhat conflicting, well-controlled randomized studies suggest that, when controlled for total energy expenditure, moderate-intensity aerobic exercise improves insulin sensitivity more than vigorous-intensity aerobic exercise. The mechanisms underlying this difference are largely unknown. One possible explanation involves enhanced metabolism of fatty acid stores in the skeletal muscle by moderate-intensity exercise, which may directly improve insulin sensitivity. Overall, new technologic and physiologic investigative tools are beginning to shed light on the biology. Further understanding of these mechanisms will lead to better understanding of the clinical implications of a healthy lifestyle and may ultimately offer new therapeutic targets for common medical conditions such as insulin resistance and diabetes.
Collapse
Affiliation(s)
- Robert W McGarrah
- Duke Molecular Physiology Institute, Duke University Medical Center, 300 North Duke Street, Durham, NC, 27701, USA. .,Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC, USA.
| | - Cris A Slentz
- Duke Molecular Physiology Institute, Duke University Medical Center, 300 North Duke Street, Durham, NC, 27701, USA
| | - William E Kraus
- Duke Molecular Physiology Institute, Duke University Medical Center, 300 North Duke Street, Durham, NC, 27701, USA.,Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC, USA
| |
Collapse
|
|
7
|
Fisher G, Windham ST, Griffin P, Warren JL, Gower BA, Hunter GR. Associations of human skeletal muscle fiber type and insulin sensitivity, blood lipids, and vascular hemodynamics in a cohort of premenopausal women. Eur J Appl Physiol 2017; 117:1413-1422. [PMID: 28497385 DOI: 10.1007/s00421-017-3634-9] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2017] [Accepted: 05/04/2017] [Indexed: 02/06/2023]
Abstract
PURPOSE Cardiometabolic disease remains a leading cause of morbidity and mortality in developed nations. Consequently, identifying and understanding factors associated with underlying pathophysiological processes leading to chronic cardio metabolic conditions is critical. Metabolic health, arterial elasticity, and insulin sensitivity (SI) may impact disease risk, and may be determined in part by myofiber type. Therefore, the purpose of this study was to test the hypothesis that type I myofiber composition would be associated with high SI, greater arterial elasticity, lower blood pressure, and blood lipids; whereas, type IIx myofibers would be associated with lower SI, lower arterial elasticity, higher blood pressure, blood lipids. METHODS Muscle biopsies were performed on the vastus lateralis in 16 subjects (BMI = 27.62 ± 4.71 kg/m2, age = 32.24 ± 6.37 years, 43% African American). The distribution of type I, IIa, and IIx myofibers was determined via immunohistochemistry performed on frozen cross-sections. Pearson correlation analyses were performed to assess associations between myofiber composition, SI, arterial elasticity, blood pressure, and blood lipid concentrations. RESULTS The percentage of type I myofibers positively correlated with SI and negatively correlated with systolic blood pressure SBP, diastolic blood pressure, and mean arterial pressure (MAP); whereas, the percentage of type IIx myofibers were negatively correlated with SI and large artery elasticity, and positively correlated with LDL cholesterol, SBP, and MAP. CONCLUSIONS These data demonstrate a potential link between myofiber composition and cardiometabolic health outcomes in a cohort of premenopausal women. Future research is needed to determine the precise mechanisms in which myofiber composition impacts the pathophysiology of impaired glucose and lipid metabolism, as well as vascular dysfunction.
Collapse
Affiliation(s)
- Gordon Fisher
- Departments of Human Studies, University of Alabama at Birmingham, Birmingham, USA.
| | - Samuel T Windham
- Department of Surgery, University of Alabama at Birmingham, Birmingham, USA
| | - Perry Griffin
- Departments of Human Studies, University of Alabama at Birmingham, Birmingham, USA
| | - Jonathan L Warren
- Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, USA
| | - Barbara A Gower
- Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, USA
| | - Gary R Hunter
- Departments of Human Studies, University of Alabama at Birmingham, Birmingham, USA
| |
Collapse
|
|
8
|
Møller CL, Kjøbsted R, Enriori PJ, Jensen TE, Garcia-Rudaz C, Litwak SA, Raun K, Wojtaszewski J, Wulff BS, Cowley MA. α-MSH Stimulates Glucose Uptake in Mouse Muscle and Phosphorylates Rab-GTPase-Activating Protein TBC1D1 Independently of AMPK. PLoS One 2016; 11:e0157027. [PMID: 27467141 PMCID: PMC4965092 DOI: 10.1371/journal.pone.0157027] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2016] [Accepted: 05/24/2016] [Indexed: 12/21/2022] Open
Abstract
The melanocortin system includes five G-protein coupled receptors (family A) defined as MC1R-MC5R, which are stimulated by endogenous agonists derived from proopiomelanocortin (POMC). The melanocortin system has been intensely studied for its central actions in body weight and energy expenditure regulation, which are mainly mediated by MC4R. The pituitary gland is the source of various POMC-derived hormones released to the circulation, which raises the possibility that there may be actions of the melanocortins on peripheral energy homeostasis. In this study, we examined the molecular signaling pathway involved in α-MSH-stimulated glucose uptake in differentiated L6 myotubes and mouse muscle explants. In order to examine the involvement of AMPK, we investigate α-MSH stimulation in both wild type and AMPK deficient mice. We found that α-MSH significantly induces phosphorylation of TBC1 domain (TBC1D) family member 1 (S237 and T596), which is independent of upstream PKA and AMPK. We find no evidence to support that α-MSH-stimulated glucose uptake involves TBC1D4 phosphorylation (T642 and S704) or GLUT4 translocation.
Collapse
Affiliation(s)
| | - Rasmus Kjøbsted
- Section of Molecular Physiology, August Krogh Centre, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Pablo J. Enriori
- Monash Obesity & Diabetes Institute, Metabolic Neurophysiology Laboratory, Monash University, 3168 Clayton, Australia
| | - Thomas Elbenhardt Jensen
- Section of Molecular Physiology, August Krogh Centre, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Cecilia Garcia-Rudaz
- Department of Pediatrics, Centenary Hospital for Women, Youth and Children and Australian National University, 2605 Canberra, Australia
| | - Sara A. Litwak
- Monash Obesity & Diabetes Institute, Metabolic Neurophysiology Laboratory, Monash University, 3168 Clayton, Australia
| | - Kirsten Raun
- Incretin and Obesity Biology, Novo Nordisk A/S, 2760 Maaloev, Denmark
| | - Jørgen Wojtaszewski
- Section of Molecular Physiology, August Krogh Centre, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, 2200 Copenhagen, Denmark
| | | | - Michael A. Cowley
- Monash Obesity & Diabetes Institute, Metabolic Neurophysiology Laboratory, Monash University, 3168 Clayton, Australia
| |
Collapse
|
|
9
|
Yu H, Fujii NL, Toyoda T, An D, Farese RV, Leitges M, Hirshman MF, Mul JD, Goodyear LJ. Contraction stimulates muscle glucose uptake independent of atypical PKC. Physiol Rep 2015; 3:3/11/e12565. [PMID: 26564060 PMCID: PMC4673624 DOI: 10.14814/phy2.12565] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Exercise increases skeletal muscle glucose uptake, but the underlying mechanisms are only partially understood. The atypical protein kinase C (PKC) isoforms λ and ζ (PKC‐λ/ζ) have been shown to be necessary for insulin‐, AICAR‐, and metformin‐stimulated glucose uptake in skeletal muscle, but not for treadmill exercise‐stimulated muscle glucose uptake. To investigate if PKC‐λ/ζ activity is required for contraction‐stimulated muscle glucose uptake, we used mice with tibialis anterior muscle‐specific overexpression of an empty vector (WT), wild‐type PKC‐ζ (PKC‐ζWT), or an enzymatically inactive T410A‐PKC‐ζ mutant (PKC‐ζT410A). We also studied skeletal muscle‐specific PKC‐λ knockout (MλKO) mice. Basal glucose uptake was similar between WT, PKC‐ζWT, and PKC‐ζT410A tibialis anterior muscles. In contrast, in situ contraction‐stimulated glucose uptake was increased in PKC‐ζT410A tibialis anterior muscles compared to WT or PKC‐ζWT tibialis anterior muscles. Furthermore, in vitro contraction‐stimulated glucose uptake was greater in soleus muscles of MλKO mice than WT controls. Thus, loss of PKC‐λ/ζ activity increases contraction‐stimulated muscle glucose uptake. These data clearly demonstrate that PKC‐λ/ζ activity is not necessary for contraction‐stimulated glucose uptake.
Collapse
Affiliation(s)
- Haiyan Yu
- Harvard Medical School, Joslin Diabetes Center, Boston, Massachusetts
| | - Nobuharu L Fujii
- Harvard Medical School, Joslin Diabetes Center, Boston, Massachusetts
| | - Taro Toyoda
- Harvard Medical School, Joslin Diabetes Center, Boston, Massachusetts
| | - Ding An
- Harvard Medical School, Joslin Diabetes Center, Boston, Massachusetts
| | | | - Michael Leitges
- The Biotechnology Center of Oslo, University of Oslo, Blindern, Oslo, Norway
| | | | - Joram D Mul
- Harvard Medical School, Joslin Diabetes Center, Boston, Massachusetts
| | - Laurie J Goodyear
- Harvard Medical School, Joslin Diabetes Center, Boston, Massachusetts
| |
Collapse
|
|
10
|
Nielsen J, Farup J, Rahbek SK, de Paoli FV, Vissing K. Enhanced Glycogen Storage of a Subcellular Hot Spot in Human Skeletal Muscle during Early Recovery from Eccentric Contractions. PLoS One 2015; 10:e0127808. [PMID: 25996774 PMCID: PMC4440641 DOI: 10.1371/journal.pone.0127808] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2015] [Accepted: 04/18/2015] [Indexed: 12/22/2022] Open
Abstract
Unaccustomed eccentric exercise is accompanied by muscle damage and impaired glucose uptake and glycogen synthesis during subsequent recovery. Recently, it was shown that the role and regulation of glycogen in skeletal muscle are dependent on its subcellular localization, and that glycogen synthesis, as described by the product of glycogen particle size and number, is dependent on the time course of recovery after exercise and carbohydrate availability. In the present study, we investigated the subcellular distribution of glycogen in fibers with high (type I) and low (type II) mitochondrial content during post-exercise recovery from eccentric contractions. Analysis was completed on five male subjects performing an exercise bout consisting of 15 x 10 maximal eccentric contractions. Carbohydrate-rich drinks were subsequently ingested throughout a 48 h recovery period and muscle biopsies for analysis included time points 3, 24 and 48 h post exercise from the exercising leg, whereas biopsies corresponding to prior to and at 48 h after the exercise bout were collected from the non-exercising, control leg. Quantitative imaging by transmission electron microscopy revealed an early (post 3 and 24 h) enhanced storage of intramyofibrillar glycogen (defined as glycogen particles located within the myofibrils) of type I fibers, which was associated with an increase in the number of particles. In contrast, late in recovery (post 48 h), intermyofibrillar, intramyofibrillar and subsarcolemmal glycogen in both type I and II fibers were lower in the exercise leg compared with the control leg, and this was associated with a smaller size of the glycogen particles. We conclude that in the carbohydrate-supplemented state, the effect of eccentric contractions on glycogen metabolism depends on the subcellular localization, muscle fiber’s oxidative capacity, and the time course of recovery. The early enhanced storage of intramyofibrillar glycogen after the eccentric contractions may entail important implications for muscle function and fatigue resistance.
Collapse
Affiliation(s)
- Joachim Nielsen
- Department of Sports Science and Clinical Biomechanics, SDU Muscle Research Cluster (SMRC), University of Southern Denmark, Odense M, Denmark
- Department of Pathology, SDU Muscle Research Cluster (SMRC), Odense University Hospital, Odense C, Denmark
- * E-mail:
| | - Jean Farup
- Section of Sport Science, Department of Public Health, Aarhus University, Aarhus, Denmark
| | - Stine Klejs Rahbek
- Section of Sport Science, Department of Public Health, Aarhus University, Aarhus, Denmark
| | | | - Kristian Vissing
- Section of Sport Science, Department of Public Health, Aarhus University, Aarhus, Denmark
| |
Collapse
|
|
11
|
Successive exposure to moderate hypoxia does not affect glucose metabolism and substrate oxidation in young healthy men. SPRINGERPLUS 2014; 3:370. [PMID: 25089253 PMCID: PMC4117865 DOI: 10.1186/2193-1801-3-370] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/29/2014] [Accepted: 07/03/2014] [Indexed: 12/03/2022]
Abstract
Introduction Exposure to hypoxia has been suggested to acutely alter glucose regulation. However, the effects of successive exposure to moderate hypoxia on postprandial glucose regulation and substrate oxidation pattern after multiple meals have not been elucidated. Purpose We examined the effects of successive exposure to moderate hypoxia on metabolic responses and substrate oxidation pattern. Methods Eight healthy men (21.0 ± 0.6 yrs, 173 ± 2.3 cm, 70.6 ± 5.0 kg, 23.4 ± 1.1 kg/m2) completed two experimental trials on separate days: a rest trial under normoxic conditions (FiO2 = 20.9%) and a rest trial under hypoxic conditions (FiO2 = 15.0%). Experimental trials were performed over 7 h in an environmental chamber. Blood and respiratory gas samples were collected over 7 h. Standard meals were provided 1 h (745 kcal) and 4 h (731 kcal) after entering the chamber. Results Although each meal significantly increased blood glucose and serum insulin concentrations (P < 0.05), these responses did not differ significantly between the trials. There were no significant differences in areas under the curves for glucose or insulin concentrations over 7 h between the trials. No significant differences were observed in blood lactate, serum cortisol, free fatty acid, or glycerol concentrations over 7 h between the trials. The oxygen consumption (
) and carbon dioxide production (
) 3 h after entering the chamber were significantly higher in the hypoxic trial than in the normoxic trial (P < 0.05). However, the differences did not affect respiratory exchange ratio (RER). The average values of
,
, and RER did not differ between the trials. Conclusion Seven hours of moderate hypoxia did not alter postprandial glucose responses or substrate oxidation in young healthy men.
Collapse
|
|
12
|
Sugar flux through the flight muscles of hovering vertebrate nectarivores: a review. J Comp Physiol B 2014; 184:945-59. [PMID: 25031038 DOI: 10.1007/s00360-014-0843-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2014] [Revised: 06/15/2014] [Accepted: 06/20/2014] [Indexed: 12/28/2022]
Abstract
In most vertebrates, uptake and oxidation of circulating sugars by locomotor muscles rises with increasing exercise intensity. However, uptake rate by muscle plateaus at moderate aerobic exercise intensities and intracellular fuels dominate at oxygen consumption rates of 50% of maximum or more. Further, uptake and oxidation of circulating fructose by muscle is negligible. In contrast, hummingbirds and nectar bats are capable of fueling expensive hovering flight exclusively, or nearly completely, with dietary sugar. In addition, hummingbirds and nectar bats appear capable of fueling hovering flight completely with fructose. Three crucial steps are believed to be rate limiting to muscle uptake of circulating glucose or fructose in vertebrates: (1) delivery to muscle; (2) transport into muscle through glucose transporter proteins (GLUTs); and (3) phosphorylation of glucose by hexokinase (HK) within the muscle. In this review, we summarize what is known about the functional upregulation of exogenous sugar flux at each of these steps in hummingbirds and nectar bats. High cardiac output, capillary density, and blood sugar levels in hummingbirds and bats enhance sugar delivery to muscles (step 1). Hummingbird and nectar bat flight muscle fibers have relatively small cross-sectional areas and thus relatively high surface areas across which transport can occur (step 2). Maximum HK activities in each species are enough for carbohydrate flux through glycolysis to satisfy 100 % of hovering oxidative demand (step 3). However, qualitative patterns of GLUT expression in the muscle (step 2) raise more questions than they answer regarding sugar transport in hummingbirds and suggest major differences in the regulation of sugar flux compared to nectar bats. Behavioral and physiological similarities among hummingbirds, nectar bats, and other vertebrates suggest enhanced capacities for exogenous fuel use during exercise may be more wide spread than previously appreciated. Further, how the capacity for uptake and phosphorylation of circulating fructose is enhanced remains a tantalizing unknown.
Collapse
|
|
13
|
Abstract
Glucose is an important fuel for contracting muscle, and normal glucose metabolism is vital for health. Glucose enters the muscle cell via facilitated diffusion through the GLUT4 glucose transporter which translocates from intracellular storage depots to the plasma membrane and T-tubules upon muscle contraction. Here we discuss the current understanding of how exercise-induced muscle glucose uptake is regulated. We briefly discuss the role of glucose supply and metabolism and concentrate on GLUT4 translocation and the molecular signaling that sets this in motion during muscle contractions. Contraction-induced molecular signaling is complex and involves a variety of signaling molecules including AMPK, Ca(2+), and NOS in the proximal part of the signaling cascade as well as GTPases, Rab, and SNARE proteins and cytoskeletal components in the distal part. While acute regulation of muscle glucose uptake relies on GLUT4 translocation, glucose uptake also depends on muscle GLUT4 expression which is increased following exercise. AMPK and CaMKII are key signaling kinases that appear to regulate GLUT4 expression via the HDAC4/5-MEF2 axis and MEF2-GEF interactions resulting in nuclear export of HDAC4/5 in turn leading to histone hyperacetylation on the GLUT4 promoter and increased GLUT4 transcription. Exercise training is the most potent stimulus to increase skeletal muscle GLUT4 expression, an effect that may partly contribute to improved insulin action and glucose disposal and enhanced muscle glycogen storage following exercise training in health and disease.
Collapse
Affiliation(s)
- Erik A Richter
- Molecular Physiology Group, Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark.
| | | |
Collapse
|
|
14
|
|
|
15
|
Talanian JL, Holloway GP, Snook LA, Heigenhauser GJF, Bonen A, Spriet LL. Exercise training increases sarcolemmal and mitochondrial fatty acid transport proteins in human skeletal muscle. Am J Physiol Endocrinol Metab 2010; 299:E180-8. [PMID: 20484014 DOI: 10.1152/ajpendo.00073.2010] [Citation(s) in RCA: 102] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Fatty acid oxidation is highly regulated in skeletal muscle and involves several sites of regulation, including the transport of fatty acids across both the plasma and mitochondrial membranes. Transport across these membranes is recognized to be primarily protein mediated, limited by the abundance of fatty acid transport proteins on the respective membranes. In recent years, evidence has shown that fatty acid transport proteins move in response to acute and chronic perturbations; however, in human skeletal muscle the localization of fatty acid transport proteins in response to training has not been examined. Therefore, we determined whether high-intensity interval training (HIIT) increased total skeletal muscle, sarcolemmal, and mitochondrial membrane fatty acid transport protein contents. Ten untrained females (22 +/- 1 yr, 65 +/- 2 kg; .VO(2peak): 2.8 +/- 0.1 l/min) completed 6 wk of HIIT, and biopsies from the vastus lateralis muscle were taken before training, and following 2 and 6 wk of HIIT. Training significantly increased maximal oxygen uptake at 2 and 6 wk (3.1 +/- 0.1, 3.3 +/- 0.1 l/min). Training for 6 wk increased FAT/CD36 at the whole muscle (10%) and mitochondrial levels (51%) without alterations in sarcolemmal content. Whole muscle plasma membrane fatty acid binding protein (FABPpm) also increased (48%) after 6 wk of training, but in contrast to FAT/CD36, sarcolemmal FABPpm increased (23%), whereas mitochondrial FABPpm was unaltered. The changes on sarcolemmal and mitochondrial membranes occurred rapidly, since differences (< or =2 wk) were not observed between 2 and 6 wk. This is the first study to demonstrate that exercise training increases fatty acid transport protein content in whole muscle (FAT/CD36 and FABPpm) and sarcolemmal (FABPpm) and mitochondrial (FAT/CD36) membranes in human skeletal muscle of females. These results suggest that increases in skeletal muscle fatty acid oxidation following training are related in part to changes in fatty acid transport protein content and localization.
Collapse
Affiliation(s)
- Jason L Talanian
- Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada.
| | | | | | | | | | | |
Collapse
|
|
16
|
Abstract
Skeletal muscle is the major tissue for postprandial glucose disposal. Facilitated glucose uptake into muscle fibers is mediated by increases in surface membrane levels of the glucose transporter GLUT4 via insulin- and/or muscle contraction-mediated GLUT4 translocation. However, the regulatory mechanisms controlling GLUT4 translocation in skeletal muscle have been difficult to characterize at the cell biology level due to muscle tissue complexity. Muscle cell culture models have improved our understanding of GLUT4 translocation and glucose transport regulation, but in vitro muscle models lack many of the characteristics of mature muscle fibers. Thus, the molecular and cellular details of GLUT4 translocation in mature skeletal muscle are deficient. The objective of this review is to highlight how advances in recent experimental approaches translate into an enhanced understanding of the regulation of GLUT4 translocation and glucose transport in mature skeletal muscle.
Collapse
Affiliation(s)
- Hans P M M Lauritzen
- Integrative Physiology and Metabolism, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215, USA.
| | | |
Collapse
|
|
17
|
Kelly KR, Williamson DL, Fealy CE, Kriz DA, Krishnan RK, Huang H, Ahn J, Loomis JL, Kirwan JP. Acute altitude-induced hypoxia suppresses plasma glucose and leptin in healthy humans. Metabolism 2010; 59:200-5. [PMID: 19765784 PMCID: PMC2813366 DOI: 10.1016/j.metabol.2009.07.014] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2009] [Revised: 07/10/2009] [Accepted: 07/15/2009] [Indexed: 01/03/2023]
Abstract
To examine the effects of acute altitude-induced hypoxia on the hormonal and metabolic response to ingested glucose, 8 young, healthy subjects (5 men and 3 women; age, 26 +/- 2 years; body mass index, 23.1 +/- 1.0 kg/m(2)) performed 2 randomized trials in a hypobaric chamber where a 75-g glucose solution was ingested under simulated altitude (ALT, 4300 m) or ambient (AMB, 362 m) conditions. Plasma glucose, insulin, C-peptide, epinephrine, leptin, and lactate concentrations were measured at baseline and 30, 60, 90, and 120 minutes after glucose ingestion during both trials. Compared with AMB, the plasma glucose response to glucose ingestion was reduced during the ALT trial (P = .04). There were no differences in the insulin and C-peptide responses between trials or in insulin sensitivity based on the homeostasis model assessment of insulin resistance. Epinephrine and lactate were both elevated during the ALT trial (P < .05), whereas the plasma leptin response was reduced compared with AMB (P < .05). The data suggest that the plasma glucose response is suppressed at ALT, but this is not due to insulin per se because insulin and C-peptide levels were similar for both trials. Elevated plasma epinephrine and lactate during ALT are indicative of increased glycogenolysis, which may have masked the magnitude of the reduced glucose response. We conclude that, during acute altitude exposure, there is a rapid metabolic response that is accompanied by a shift in the hormonal milieu that appears to favor increased glucose utilization.
Collapse
Affiliation(s)
- Karen R. Kelly
- Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195
- Department of Nutrition, Case Western Reserve University School of Medicine, Cleveland, OH 44109
| | - David L. Williamson
- Division of Exercise Physiology, West Virginia University School of Medicine, Morgantown, WV 26506
| | - Ciarán E. Fealy
- Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195
| | - David A. Kriz
- Noll Physiological Research Center, Pennsylvania State University, University Park, PA 16802
| | - Raj K. Krishnan
- Noll Physiological Research Center, Pennsylvania State University, University Park, PA 16802
| | - Hazel Huang
- Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195
| | - Janice Ahn
- Department of Nutrition, Case Western Reserve University School of Medicine, Cleveland, OH 44109
| | - Joseph L. Loomis
- Noll Physiological Research Center, Pennsylvania State University, University Park, PA 16802
| | - John P. Kirwan
- Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195
- Department of Nutrition, Case Western Reserve University School of Medicine, Cleveland, OH 44109
- Department of Gastroenterology/Hepatology, Cleveland Clinic, Cleveland, OH 44195
- Department of Physiology, Case Western Reserve University School of Medicine, Cleveland, OH 44109
| |
Collapse
|
|
18
|
Ploug T, Vinten J. Counterpoint: Glucose phosphorylation is not a significant barrier to glucose uptake by the working muscle. J Appl Physiol (1985) 2007; 101:1805-6; discussion 1806-8. [PMID: 17106069 DOI: 10.1152/japplphysiol.00817b.2006] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Affiliation(s)
- Thorkil Ploug
- Copenhagen Muscle Research Centre, Department of Medical Physiology, The Panum Institute, University of Copenhagen, Denmark.
| | | |
Collapse
|
|
19
|
REBUTTAL FROM DRS. PLOUG AND VINTEN. J Appl Physiol (1985) 2006. [DOI: 10.1152/japplphysiol.00817d.2006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
|
|
20
|
Abstract
Carbohydrate supplementation in prolonged aerobic exercise has been shown to be effective in improving performance and deferring fatigue. However, there is confounding evidence with regard to carbohydrate supplementation and tennis performance, which may be due to the limited number of studies on this topic. This evidence based review, using database searches of Medline and SPORTDiscus, summarises the limited relevant literature to determine if carbohydrate supplementation benefits tennis performance, and, if so, the appropriate amounts and timing. Although more research is required, it appears that it may be beneficial in tennis sessions lasting more than 90 minutes.
Collapse
Affiliation(s)
- M S Kovacs
- Department of Kinesiology, University of Alabama, Tuscaloosa, AL 35487, USA.
| |
Collapse
|
|
21
|
Rose AJ, Richter EA. Skeletal muscle glucose uptake during exercise: how is it regulated? Physiology (Bethesda) 2005; 20:260-70. [PMID: 16024514 DOI: 10.1152/physiol.00012.2005] [Citation(s) in RCA: 221] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
The increase in skeletal muscle glucose uptake during exercise results from a coordinated increase in rates of glucose delivery (higher capillary perfusion), surface membrane glucose transport, and intracellular substrate flux through glycolysis. The mechanism behind the movement of GLUT4 to surface membranes and the subsequent increase in transport by muscle contractions is largely unresolved, but it is likely to occur through intracellular signaling involving Ca(2+)-calmodulin-dependent protein kinase, 5'-AMP-activated protein kinase, and possibly protein kinase C.
Collapse
Affiliation(s)
- Adam J Rose
- Department of Human Physiology, Institute of Exercise and Sport Sciences, Copenhagen Muscle Research Centre, University of Copenhagen, Copenhagen, Denmark
| | | |
Collapse
|
|
22
|
Abstract
Exercise/muscle contraction activates glucose transport. The increase in muscle glucose transport induced by exercise is independent of insulin. As the acute effect of exercise on glucose transport wears off, it is replaced by an increase in insulin sensitivity. An increase in insulin sensitivity results in a shift in the insulin dose-response curve to the left, with a decrease in the concentration of insulin needed to induce 50% of the maximal response. This phenomenon, which plays a major role in rapid muscle glycogen accumulation after exercise, is not mediated by amplification of the insulin signal. Development of the increase in insulin sensitivity after contractions does not require protein synthesis or activation of p38 MAPK. It does require the presence of a serum protein during the period of contractile activity. The effect of exercise on muscle insulin sensitivity is mimicked by hypoxia and by treatment of muscles with 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside to activate AMP-activated protein kinase. The postexercise increase in sensitivity of muscle glucose transport to activation is not specific for insulin but also involves an increased susceptibility to activation by a submaximal contraction/hypoxia stimulus. The increase in insulin sensitivity is mediated by translocation of more GLUT4 glucose transporters to the cell surface in response to a submaximal insulin stimulus. Although the postexercise increase in muscle insulin sensitivity has been characterized in considerable detail, the basic mechanisms underlying this phenomenon remain a mystery.
Collapse
Affiliation(s)
- John O Holloszy
- Division of Geriatrics and Nutritional Sciences, Department of Internal Medicine, Washington Univ. School of Medicine, 4566 Scott Ave., Campus Box 8113, St. Louis, MO 63110, USA.
| |
Collapse
|
|
23
|
Abstract
Participants in the sport of bodybuilding are judged by appearance rather than performance. In this respect, increased muscle size and definition are critical elements of success. The purpose of this review is to evaluate the literature and provide recommendations regarding macronutrient intake during both 'off-season' and 'pre-contest' phases. Body builders attempt to increase muscle mass during the off-season (no competitive events), which may be the great majority of the year. During the off-season, it is advantageous for the bodybuilder to be in positive energy balance so that extra energy is available for muscle anabolism. Additionally, during the off-season, adequate protein must be available to provide amino acids for protein synthesis. For 6-12 weeks prior to competition, body builders attempt to retain muscle mass and reduce body fat to very low levels. During the pre-contest phase, the bodybuilder should be in negative energy balance so that body fat can be oxidised. Furthermore, during the pre-contest phase, protein intake must be adequate to maintain muscle mass. There is evidence that a relatively high protein intake (approximately 30% of energy intake) will reduce lean mass loss relative to a lower protein intake (approximately 15% of energy intake) during energy restriction. The higher protein intake will also provide a relatively large thermic effect that may aid in reducing body fat. In both the off-season and pre-contest phases, adequate dietary carbohydrate should be ingested (55-60% of total energy intake) so that training intensity can be maintained. Excess dietary saturated fat can exacerbate coronary artery disease; however, low-fat diets result in a reduction in circulating testosterone. Thus, we suggest dietary fats comprise 15-20% of the body builders' off-season and pre-contest diets. Consumption of protein/amino acids and carbohydrate immediately before and after training sessions may augment protein synthesis, muscle glycogen resynthesis and reduce protein degradation. The optimal rate of carbohydrate ingested immediately after a training session should be 1.2 g/kg/hour at 30-minute intervals for 4 hours and the carbohydrate should be of high glycaemic index. In summary, the composition of diets for body builders should be 55-60% carbohydrate, 25-30% protein and 15-20% of fat, for both the off-season and pre-contest phases. During the off-season the diet should be slightly hyperenergetic (approximately 15% increase in energy intake) and during the pre-contest phase the diet should be hypoenergetic (approximately 15% decrease in energy intake).
Collapse
Affiliation(s)
- Charles P Lambert
- Nutrition, Metabolism, and Exercise Laboratory, Donald W. Reynolds Center on Aging, Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
| | | | | |
Collapse
|
|
24
|
Ai H, Ralston E, Lauritzen HPMM, Galbo H, Ploug T. Disruption of microtubules in rat skeletal muscle does not inhibit insulin- or contraction-stimulated glucose transport. Am J Physiol Endocrinol Metab 2003; 285:E836-44. [PMID: 12746214 DOI: 10.1152/ajpendo.00238.2002] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Insulin and muscle contractions stimulate glucose transport in skeletal muscle through a translocation of intracellular GLUT4 glucose transporters to the cell surface. Judged by immunofluorescence microscopy, part of the GLUT4 storage sites is associated with the extensive microtubule cytoskeleton found in all muscle fibers. Here, we test whether microtubules are required mediators of the effect of insulin and contractions. In three different incubated rat muscles with distinct fiber type composition, depolymerization of microtubules with colchicine for < or =8 h did not inhibit insulin- or contraction-stimulated 2-deoxyglucose transport or force production. On the contrary, colchicine at least partially prevented the approximately 30% decrease in insulin-stimulated transport that specifically developed during 8 h of incubation in soleus muscle but not in flexor digitorum brevis or epitrochlearis muscles. In contrast, nocodazole, another microtubule-disrupting drug, rapidly and dose dependently blocked insulin- and contraction-stimulated glucose transport. A similar discrepancy between colchicine and nocodazole was also found in their ability to block glucose transport in muscle giant "ghost" vesicles. This suggests that the ability of insulin and contractions to stimulate glucose transport in muscle does not require an intact microtubule network and that nocodazole inhibits glucose transport independently of its microtubule-disrupting effect.
Collapse
Affiliation(s)
- Hua Ai
- Copenhagen Muscle Research Center, Department of Medical Physiology, The Panum Institute, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark
| | | | | | | | | |
Collapse
|
|
25
|
Wojtaszewski JFP, Nielsen JN, Richter EA. Invited review: effect of acute exercise on insulin signaling and action in humans. J Appl Physiol (1985) 2002; 93:384-92. [PMID: 12070228 DOI: 10.1152/japplphysiol.00043.2002] [Citation(s) in RCA: 76] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
After a single bout of exercise, insulin action is increased in the muscles that were active during exercise. The increased insulin action has been shown to involve glucose transport, glycogen synthesis, and glycogen synthase (GS) activation as well as amino acid transport. A major mechanism involved in increased insulin stimulation of glucose uptake after exercise seems to be the exercise-associated decrease in muscle glycogen content. Muscle glycogen content also plays a pivotal role for the activity of GS and for the ability of insulin to increase GS activity. Insulin signaling in human skeletal muscle is activated by physiological insulin concentrations, but the increase in insulin action after exercise does not seem to be related to increased insulin signaling [insulin receptor tyrosine kinase activity, insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation (RS1), IRS-1-associated phosphatidylinositol 3-kinase activity, Akt phosphorylation (Ser(473)), glycogen synthase kinase 3 (GSK3) phosphorylation (Ser(21)), and GSK3alpha activity], as measured in muscle lysates. Furthermore, insulin signaling is also largely unaffected by exercise itself. This, however, does not preclude that exercise influences insulin signaling through changes in the spatial arrangement of the signaling compounds or by affecting unidentified signaling intermediates. Finally, 5'-AMP-activated protein kinase has recently entered the stage as a promising player in explaining at least a part of the mechanism by which exercise enhances insulin action.
Collapse
Affiliation(s)
- Jørgen F P Wojtaszewski
- Copenhagen Muscle Research Centre, Department of Human Physiology, Institute of Exercise and Sports Sciences, University of Copenhagen, Denmark
| | | | | |
Collapse
|
|
26
|
Ai H, Ihlemann J, Hellsten Y, Lauritzen HPMM, Hardie DG, Galbo H, Ploug T. Effect of fiber type and nutritional state on AICAR- and contraction-stimulated glucose transport in rat muscle. Am J Physiol Endocrinol Metab 2002; 282:E1291-300. [PMID: 12006359 DOI: 10.1152/ajpendo.00167.2001] [Citation(s) in RCA: 82] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
AMP-activated protein kinase (AMPK) may mediate the stimulatory effect of contraction and 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) on glucose transport in skeletal muscle. In muscles with different fiber type composition from fasted rats, AICAR increased 2-deoxyglucose transport and total AMPK activity approximately twofold in epitrochlearis (EPI), less in flexor digitorum brevis, and not at all in soleus muscles. Contraction increased both transport and AMPK activity more than AICAR did. In EPI muscles, the effects of AICAR and contractions on glucose transport were partially additive despite a lower AMPK activity with AICAR compared with contraction alone. In EPI from fed rats, glucose transport responses were smaller than what was seen in fasted rats, and AICAR did not increase transport despite an increase in AMPK activity. AICAR and contraction activated both alpha(1)- and alpha(2)-isoforms of AMPK. Expression of both isoforms varied with fiber types, and alpha(2) was highly expressed in nuclei. In conclusion, AICAR-stimulated glucose transport varies with muscle fiber type and nutritional state. AMPK is unlikely to be the sole mediator of contraction-stimulated glucose transport.
Collapse
Affiliation(s)
- Hua Ai
- Copenhagen Muscle Research Centre, Department of Medical Physiology, Panum Institute, DK-2200, Copenhagen, Denmark
| | | | | | | | | | | | | |
Collapse
|
|
27
|
Campbell SE, Febbraio MA. Effect of the ovarian hormones on GLUT4 expression and contraction-stimulated glucose uptake. Am J Physiol Endocrinol Metab 2002; 282:E1139-46. [PMID: 11934680 DOI: 10.1152/ajpendo.00184.2001] [Citation(s) in RCA: 91] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
This study examined the roles of the female sex steroids, 17beta-estradiol (E(2)) and progesterone (Prog), on glucose uptake and GLUT4 protein expression. Female Sprague-Dawley rats were either sham operated (C) or ovariectomized and treated with placebo (O), E(2) (E), Prog (P), or both hormones at physiological doses (P + E) or the same dose of Prog with a high dose of E(2) (P + HiE) via timed-release pellets inserted at the time of surgery, 15 days before metabolic testing. On the morning of day 15, animals received a 300-microCi injection (ip) of 2-deoxy-[(14)C]glucose and then either exercised on a motorized treadmill for 30 min at 0.35 m/s or remained sedentary in their cages for the same period. Basal glucose uptake was not different between the treatment groups in either the red or white quadriceps. However, glucose uptake was decreased (P < 0.05) in O, P, and P + E rats during exercise in the red quadriceps compared with C rats, whereas E and P + HiE treatment restored glucose uptake. Glycogen content in skeletal muscle followed similar trends, with no differences seen in resting animals. Postexercise red quadriceps glycogen levels were higher (P < 0.05) in the E and P + HiE rats compared with O and P. Treatment of ovariectomized rats with progesterone (P rats) decreased (P < 0.05) GLUT4 content in the red quadriceps by 21% compared with C rats. These data demonstrate that estrogen-deficient animals have a decreased ability for contraction-stimulated glucose uptake and increased glycogen use during aerobic exercise. However, changes in contraction-stimulated glucose uptake could not be explained by altered transporter protein content, since the absence of E(2) had no effect on GLUT4 protein.
Collapse
Affiliation(s)
- S E Campbell
- Department of Physiology, The University of Melbourne, Parkville, Victoria 3010, Australia
| | | |
Collapse
|
|
28
|
Klip A, Marette A. Regulation of Glucose Transporters by Insulin and Exercise: Cellular Effects and Implications for Diabetes. Compr Physiol 2001. [DOI: 10.1002/cphy.cp070214] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
|
|
29
|
Abstract
Growing evidence suggests that the ovarian hormones have major effects on lipid and carbohydrate metabolism, and may also play a major role in up-stream molecular signaling mechanisms for regulating substrate metabolism. It appears that the absence of estrogen can impair glucose uptake during exercise. In contrast, progesterone not only impairs contraction-mediated glucose uptake when solely administered, but impairs glucose uptake when physiological concentrations of both estrogen and progesterone are administered. Likewise, progesterone administered to rodents for 14 days decreases glucose transporter (GLUT) 4 protein content in skeletal muscle and adipose tissue. Furthermore removing the ovaries decreases the activity of key oxidative enzymes while estrogen treatment restores the activity of these enzymes. It appears, therefore, that estrogen increases the metabolic capacity for both carbohydrate and lipid metabolism, perhaps increasing the overall metabolic flexibility of skeletal muscle. Conversely, progesterone negates both these effects, and could therefore result in a state of relative metabolic inflexibility, similar to that observed in the metabolic syndrome.
Collapse
Affiliation(s)
- S E Campbell
- Department of Kinesiology, University of Waterloo, Waterloo, Ontario, Canada
| | | |
Collapse
|
|
30
|
Aslesen R, Engebretsen EM, Franch J, Jensen J. Glucose uptake and metabolic stress in rat muscles stimulated electrically with different protocols. J Appl Physiol (1985) 2001; 91:1237-44. [PMID: 11509521 DOI: 10.1152/jappl.2001.91.3.1237] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
In the present study, the relationship between the pattern of electrical stimulation and glucose uptake was investigated in slow-twitch muscles (soleus) and fast-twitch muscles (epitrochlearis) from Wistar rats. Muscles were stimulated electrically for 30 min in vitro with either single pulses (frequencies varied between 0.8 and 15 Hz) or with 200-ms trains (0.1-2 Hz). Glucose uptake (measured with tracer amount of 2-[(3)H]deoxyglucose) increased with increasing number of impulses whether delivered as single pulses or as short trains. The highest glucose uptake achieved with short tetanic contractions was similar in soleus and epitrochlearis (10.9 +/- 0.7 and 12.0 +/- 0.8 mmol x kg dry wt(-1) x 30 min(-1), respectively). Single pulses, on the other hand, increased contraction-stimulated glucose uptake less in soleus than in epitrochlearis (7.5 +/- 1.1 and 11.7 +/- 0.5 mmol x kg dry wt(-1) x 30 min(-1), respectively; P < 0.02). Glucose uptake correlated with glycogen breakdown in soleus (r = 0.84, P < 0.0001) and (epitrochlearis: r = 0.91, P < 0.0001). Contraction-stimulated glucose uptake also correlated with breakdown of ATP and PCr and with reduction in force. Our data suggest that metabolic stress mediates contraction-stimulated glucose uptake.
Collapse
Affiliation(s)
- R Aslesen
- Department of Anatomy, Institute of Basic Medical Sciences, University of Oslo, N-0317 Oslo, Norway
| | | | | | | |
Collapse
|
|
31
|
Zorzano A, Fandos C, Palacín M. Role of plasma membrane transporters in muscle metabolism. Biochem J 2000; 349 Pt 3:667-88. [PMID: 10903126 PMCID: PMC1221192 DOI: 10.1042/bj3490667] [Citation(s) in RCA: 62] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Muscle plays a major role in metabolism. Thus it is a major glucose-utilizing tissue in the absorptive state, and changes in muscle insulin-stimulated glucose uptake alter whole-body glucose disposal. In some conditions, muscle preferentially uses lipid substrates, such as fatty acids or ketone bodies. Furthermore, muscle is the main reservoir of amino acids and protein. The activity of many different plasma membrane transporters, such as glucose carriers and transporters of carnitine, creatine and amino acids, play a crucial role in muscle metabolism by catalysing the influx or the efflux of substrates across the cell surface. In some cases, the membrane transport process is subjected to intense regulatory control and may become a potential pharmacological target, as is the case with the glucose transporter GLUT4. The goal of this review is the molecular characterization of muscle membrane transporter proteins, as well as the analysis of their possible regulatory role.
Collapse
Affiliation(s)
- A Zorzano
- Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Av. Diagonal 645, 08028 Barcelona, Spain.
| | | | | |
Collapse
|
|
32
|
Han XX, Fernando PK, Bonen A. Denervation provokes greater reductions in insulin-stimulated glucose transport in muscle than severe diabetes. Mol Cell Biochem 2000; 210:81-9. [PMID: 10976761 DOI: 10.1023/a:1007108025929] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
We have examined the independent and combined effects of insulin insufficiency (streptozotocin (STZ)-induced diabetes, 85 mg/kg i.p.) and reduced muscle activity (denervation) (7 days) on basal, insulin-stimulated and contraction-stimulated glucose transport in rat muscles (soleus, red and white gastrocnemius). There were four treatments: control, denervated, diabetic, and denervated + diabetic muscles. Contraction-stimulated glucose transport was lowered (approximately 50%) (p < 0.05) to the same extent in all experimental groups. In contrast, there was a much smaller reduction insulin-stimulated glucose transport in muscles from diabetic animals (18-24% reduction, p < 0.05) than in denervated muscles (40-60% reduction, p < 0.05) and in denervated + diabetic muscles (40-60% reduction, p < 0.05). GLUT-4 mRNA reduction was greatest in denervated + diabetic muscles (approximately -75%, p < 0.05). GLUT-4 protein was decreased (p < 0.05) to a similar extent in all three experimental conditions (approximately -30-40%). In conclusion, (1) muscle inactivity (denervation) and STZ-induced diabetes had similar effects on reducing contraction-stimulated glucose transport, but (2) muscle inactivity (denervation), rather than severe diabetes, produced a 2-fold greater impairment in skeletal muscle insulin-stimulated glucose transport.
Collapse
Affiliation(s)
- X X Han
- Department of Kinesiology, University of Waterloo, Ontario, Canada
| | | | | |
Collapse
|
|
33
|
Seatter MJ, Gould GW. The mammalian facilitative glucose transporter (GLUT) family. PHARMACEUTICAL BIOTECHNOLOGY 2000; 12:201-28. [PMID: 10742976 DOI: 10.1007/0-306-46812-3_7] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/16/2023]
Affiliation(s)
- M J Seatter
- Division of Biochemistry and Molecular Biology, University of Glasgow, Scotland
| | | |
Collapse
|
|
34
|
Riddell MC, Bar-Or O, Hollidge-Horvat M, Schwarcz HP, Heigenhauser GJ. Glucose ingestion and substrate utilization during exercise in boys with IDDM. J Appl Physiol (1985) 2000; 88:1239-46. [PMID: 10749813 DOI: 10.1152/jappl.2000.88.4.1239] [Citation(s) in RCA: 43] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
This study was intended to compare exogenous [(13)C]glucose (Glu(exo)) oxidation in boys with insulin-dependent diabetes mellitus (IDDM) and healthy boys of similar age, weight, and maximal O(2) uptake. In a control trial with water intake (CT) and in a (13)C-enriched glucose trial (GT), subjects cycled for 60 min (58.8 +/- 0.9% maximal O(2) uptake) while the utilization of total glucose, total fat, and Glu(exo) was assessed. In CT, total glucose was 84.7 +/- 9.2 vs. 91.3 +/- 6.6 g/60 min (not significantly different) and total fat was 13.3 +/- 2.2 vs. 11.1 +/- 1.7 g/60 min (not significantly different) in IDDM vs. healthy boys, respectively. In GT, Glu(exo) was 10.4 +/- 1.7 vs. 14.8 +/- 1.1 g/60 min, corresponding to 9.0 +/- 1.0 vs. 12.4 +/- 0.5% of the total energy supply in IDDM and healthy boys, respectively (P < 0.05). Endogenous glucose was spared in both groups by 12.6 +/- 3.5% (P < 0.05). Blood glucose and plasma insulin concentrations were two- to threefold higher in IDDM vs. healthy boys in both trials. In conclusion, Glu(exo) is impaired in exercising boys with IDDM, even when plasma insulin levels are elevated.
Collapse
Affiliation(s)
- M C Riddell
- Children's Exercise and Nutrition Centre, McMaster University, Hamilton, Ontario, Canada L8N 3Z5
| | | | | | | | | |
Collapse
|
|
35
|
Wojtaszewski JF, Higaki Y, Hirshman MF, Michael MD, Dufresne SD, Kahn CR, Goodyear LJ. Exercise modulates postreceptor insulin signaling and glucose transport in muscle-specific insulin receptor knockout mice. J Clin Invest 1999; 104:1257-64. [PMID: 10545524 PMCID: PMC409827 DOI: 10.1172/jci7961] [Citation(s) in RCA: 154] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Physical exercise promotes glucose uptake into skeletal muscle and makes the working muscles more sensitive to insulin. To understand the role of insulin receptor (IR) signaling in these responses, we studied the effects of exercise and insulin on skeletal muscle glucose metabolism and insulin signaling in mice lacking insulin receptors specifically in muscle. Muscle-specific insulin receptor knockout (MIRKO) mice had normal resting 2-deoxy-glucose (2DG) uptake in soleus muscles but had no significant response to insulin. Despite this, MIRKO mice displayed normal exercise-stimulated 2DG uptake and a normal synergistic activation of muscle 2DG uptake with the combination of exercise plus insulin. Glycogen content and glycogen synthase activity in resting muscle were normal in MIRKO mice, and exercise, but not insulin, increased glycogen synthase activity. Insulin, exercise, and the combination of exercise plus insulin did not increase IR tyrosine phosphorylation or phosphatidylinositol 3-kinase activity in MIRKO muscle. In contrast, insulin alone produced a small activation of Akt and glycogen synthase kinase-3 in MIRKO mice, and prior exercise markedly enhanced this insulin effect. In conclusion, normal expression of muscle insulin receptors is not needed for the exercise-mediated increase in glucose uptake and glycogen synthase activity in vivo. The synergistic activation of glucose transport with exercise plus insulin is retained in MIRKO mice, suggesting a phenomenon mediated by nonmuscle cells or by downstream signaling events.
Collapse
Affiliation(s)
- J F Wojtaszewski
- Research Division, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02215, USA
| | | | | | | | | | | | | |
Collapse
|
|
36
|
Vandenberghe K, Richter EA, Hespel P. Regulation of glycogen breakdown by glycogen level in contracting rat muscle. ACTA PHYSIOLOGICA SCANDINAVICA 1999; 165:307-14. [PMID: 10192181 DOI: 10.1046/j.1365-201x.1999.00506.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
The interaction of glycogen concentration, insulin and beta-adrenergic stimulation in the regulation of glycogen breakdown was studied in perfused rat muscles. Rats were pre-conditioned to obtain two groups with either normal (N) or 'supercompensated' (SC) muscle glycogen. The next day their hindlimbs were perfused with a medium containing insulin (0, 40 and 100 microU mL(-1)) and/or isoproterenol (0 and 1.5 nmol L(-1)). Contractions were induced by electrical stimulation of the sciatic nerve. Compared with N, glycogen breakdown in white gastrocnemius during contractions was greater in SC at any hormonal combination (P < 0.05). Conversely, in red gastrocnemius (RG) the higher glycogenolytic rate in SC, compared with N, faded as the insulin concentration was raised from 0 to 100 microU mL(-1). However, isoproterenol restored the higher glycogenolytic rate in SC. In any condition, RG glycogen synthase fractional activity was lower (P < 0.05) during contractions in SC than in N. Furthermore, the percentage of phosphorylase a was higher in SC except when muscles were exposed to insulin alone. In conclusion, high initial glycogen concentration in fast-glycolytic muscle causes high glycogenolytic rate during contractions, irrespective of hormonal stimulation. In contrast, due to down-regulation of phosphorylase activity, such a relationship does not exist in insulin-stimulated fast-oxidative muscle.
Collapse
Affiliation(s)
- K Vandenberghe
- Department of Kinesiology, Faculty of Physical Education and Physiotherapy, Katholieke Universiteit Leuven, Heverlee, Belgium
| | | | | |
Collapse
|
|
37
|
Ploug T, van Deurs B, Ai H, Cushman SW, Ralston E. Analysis of GLUT4 distribution in whole skeletal muscle fibers: identification of distinct storage compartments that are recruited by insulin and muscle contractions. J Cell Biol 1998; 142:1429-46. [PMID: 9744875 PMCID: PMC2141761 DOI: 10.1083/jcb.142.6.1429] [Citation(s) in RCA: 220] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
The effects of insulin stimulation and muscle contractions on the subcellular distribution of GLUT4 in skeletal muscle have been studied on a preparation of single whole fibers from the rat soleus. The fibers were labeled for GLUT4 by a preembedding technique and observed as whole mounts by immunofluorescence microscopy, or after sectioning, by immunogold electron microscopy. The advantage of this preparation for cells of the size of muscle fibers is that it provides global views of the staining from one end of a fiber to the other and from one side to the other through the core of the fiber. In addition, the labeling efficiency is much higher than can be obtained with ultracryosections. In nonstimulated fibers, GLUT4 is excluded from the plasma membrane and T tubules. It is distributed throughout the muscle fibers with approximately 23% associated with large structures including multivesicular endosomes located in the TGN region, and 77% with small tubulovesicular structures. The two stimuli cause translocation of GLUT4 to both plasma membrane and T tubules. Quantitation of the immunogold electron microscopy shows that the effects of insulin and contraction are additive and that each stimulus recruits GLUT4 from both large and small depots. Immunofluorescence double labeling for GLUT4 and transferrin receptor (TfR) shows that the small depots can be further subdivided into TfR-positive and TfR-negative elements. Interestingly, we observe that colocalization of TfR and GLUT4 is increased by insulin and decreased by contractions. These results, supported by subcellular fractionation experiments, suggest that TfR-positive depots are only recruited by contractions. We do not find evidence for stimulation-induced unmasking of resident surface membrane GLUT4 transporters or for dilation of the T tubule system (Wang, W., P.A. Hansen, B.A. Marshall, J.O. Holloszy, and M. Mueckler. 1996. J. Cell Biol. 135:415-430).
Collapse
MESH Headings
- Animals
- Epitopes, B-Lymphocyte/metabolism
- Fluorescent Antibody Technique, Indirect
- Glucose Transporter Type 4
- Golgi Apparatus/metabolism
- Insulin/metabolism
- Insulin/pharmacology
- Male
- Monosaccharide Transport Proteins/metabolism
- Muscle Contraction/physiology
- Muscle Fibers, Skeletal/drug effects
- Muscle Fibers, Skeletal/metabolism
- Muscle Fibers, Skeletal/physiology
- Muscle Fibers, Skeletal/ultrastructure
- Muscle Proteins
- Muscle, Skeletal/drug effects
- Muscle, Skeletal/metabolism
- Muscle, Skeletal/physiology
- Muscle, Skeletal/ultrastructure
- Rabbits
- Rats
- Rats, Wistar
- Receptors, Transferrin/metabolism
Collapse
Affiliation(s)
- T Ploug
- Copenhagen Muscle Research Centre, Rigshospitalet, Copenhagen, Denmark.
| | | | | | | | | |
Collapse
|
|
38
|
Lund S, Holman GD, Schmitz O, Pedersen O. Contraction stimulates translocation of glucose transporter GLUT4 in skeletal muscle through a mechanism distinct from that of insulin. Proc Natl Acad Sci U S A 1995; 92:5817-21. [PMID: 7597034 PMCID: PMC41592 DOI: 10.1073/pnas.92.13.5817] [Citation(s) in RCA: 342] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
The acute effects of contraction and insulin on the glucose transport and GLUT4 glucose transporter translocation were investigated in rat soleus muscles by using a 3-O-methylglucose transport assay and the sensitive exofacial labeling technique with the impermeant photoaffinity reagent 2-N-4-(1-azi-2,2,2-trifluoroethyl)benzoyl-1,3-bis(D-mannose-4-y loxy)-2- propylamine (ATB-BMPA), respectively. Addition of wortmannin, which inhibits phosphatidylinositol 3-kinase, reduced insulin-stimulated glucose transport (8.8 +/- 0.5 mumol per ml per h vs. 1.4 +/- 0.1 mumol per ml per h) and GLUT4 translocation [2.79 +/- 0.20 pmol/g (wet muscle weight) vs. 0.49 +/- 0.05 pmol/g (wet muscle weight)]. In contrast, even at a high concentration (1 microM), wortmannin had no effect on contraction-mediated glucose uptake (4.4 +/- 0.1 mumol per ml per h vs. 4.1 +/- 0.2 mumol per ml per h) and GLUT4 cell surface content [1.75 +/- 0.16 pmol/g (wet muscle weight) vs. 1.52 +/- 0.16 pmol/g (wet muscle weight)]. Contraction-mediated translocation of the GLUT4 transporters to the cell surface was closely correlated with the glucose transport activity and could account fully for the increment in glucose uptake after contraction. The combined effects of contraction and maximal insulin stimulation were greater than either stimulation alone on glucose transport activity (11.5 +/- 0.4 mumol per ml per h vs. 5.6 +/- 0.2 mumol per ml per h and 9.0 +/- 0.2 mumol per ml per h) and on GLUT4 translocation [4.10 +/- 0.20 pmol/g (wet muscle weight) vs. 1.75 +/- 0.25 pmol/g (wet muscle weight) and 3.15 +/- 0.18 pmol/g (wet muscle weight)]. The results provide evidence that contraction stimulates translocation of GLUT4 in skeletal muscle through a mechanism distinct from that of insulin.
Collapse
Affiliation(s)
- S Lund
- Medical Research Laboratory, Aarhus Kommunehospital, Aarhus University Hospital, Denmark
| | | | | | | |
Collapse
|
|
39
|
Liu YL, Stock MJ. Acute effects of the beta 3-adrenoceptor agonist, BRL 35135, on tissue glucose utilisation. Br J Pharmacol 1995; 114:888-94. [PMID: 7773551 PMCID: PMC1510208 DOI: 10.1111/j.1476-5381.1995.tb13287.x] [Citation(s) in RCA: 46] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
1. The acute effects of BRL 35135 (BRL) on tissue glucose utilisation index (GUI) in vivo were investigated in anaesthetized rats by use of 2-deoxy-[3H]-glucose. 2. Intravenous injection of BRL caused a dose-dependent increase in GUI in skeletal muscle, and white and brown adipose tissue; plasma insulin and fatty acid concentrations were also increased. Chronic treatment with BRL added to the diet caused a 34 fold increase in basal GUI of brown adipose tissue (BAT), but had no effect on GUI in other tissues. After chronic treatment, the acute tissue response to an intravenous maximal dose of BRL had disappeared completely in all tissues apart from the soleus muscle. 3. A high dose (20 mg kg-1) of the non-selective beta-antagonist, propranolol, inhibited the acute effect of BRL on GUI in BAT, but failed to affect GUI in muscle. A lower dose (1 mg kg-1) of the antagonist also inhibited the BAT response, but had little or no effect on the response in Type I (working) muscles such as soleus and adductor longus (ADL), and potentiated the response in Type II (non-working) muscles such as tibialis and extensor digitorium longus (EDL). 4. A low dose (1 mg kg-1) of the selective beta 1-antagonist, atenolol, had no effect on the BRL response but the same dose of the selective beta 2-antagonist, ICI 118551, potentiated significantly the effect of BRL on GUI in most muscles without altering plasma insulin levels. 5. It is concluded that: (i) the heterogeneous tissue responses of different muscle fibre types in the presence of P-antagonists indicates that BRL affects muscle GUI directly, in addition to effects mediated by increases in plasma insulin concentration; (ii) the resistance of the BRL response to conventional P-adrenoceptor antagonists implicates an atypical adrenoceptor mediating the GUI response in skeletal muscle, but this may not be identical to the adipose tissue P3-adrenoceptor; (iii) the potentiation of BRL responses by ICI 118551 indicates an inhibitory P2-adrenoceptor-mediated component in the muscle GUI response to BRL.
Collapse
Affiliation(s)
- Y L Liu
- Department of Physiology, St. George's Hospital Medical School, Tooting, London
| | | |
Collapse
|
|
40
|
Wilson CM, Cushman SW. Insulin stimulation of glucose transport activity in rat skeletal muscle: increase in cell surface GLUT4 as assessed by photolabelling. Biochem J 1994; 299 ( Pt 3):755-9. [PMID: 8192664 PMCID: PMC1138085 DOI: 10.1042/bj2990755] [Citation(s) in RCA: 68] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
We have used a photoaffinity label to quantify cell surface GLUT4 glucose transporters in isolated rat soleus muscles. In this system, insulin stimulated an 8.6-fold increase in 3-O-methylglucose glucose transport, while photolabelled GLUT4 increased 8-fold. These results demonstrate that the insulin-stimulated increase in glucose transport activity in skeletal muscle can be accounted for by an increase in surface-accessible GLUT4 content.
Collapse
Affiliation(s)
- C M Wilson
- Experimental Diabetes, Metabolism, and Nutrition Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892
| | | |
Collapse
|
|
41
|
Brozinick JT, Etgen GJ, Yaspelkis BB, Ivy JL. The effects of muscle contraction and insulin on glucose-transporter translocation in rat skeletal muscle. Biochem J 1994; 297 ( Pt 3):539-45. [PMID: 8110191 PMCID: PMC1137867 DOI: 10.1042/bj2970539] [Citation(s) in RCA: 52] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
The effect of electrically induced muscle contraction, insulin (10 m-units/ml) and electrically-induced muscle contraction in the presence of insulin on insulin-regulatable glucose-transporter (GLUT-4) protein distribution was studied in female Sprague-Dawley rats during hindlimb perfusion. Plasma-membrane cytochalasin B binding increased approximately 2-fold, whereas GLUT-4 protein concentration increased approximately 1.5-fold above control with contractions, insulin, or insulin + contraction. Microsomal-membrane cytochalasin B binding and GLUT-4 protein concentration decreased by approx. 30% with insulin or insulin + contraction, but did not significantly decrease with contraction alone. The rate of muscle glucose uptake was assessed by determining the rate of 2-deoxy[3H]glucose accumulation in the soleus, plantaris, and red and white portions of the gastrocnemius. Both contraction and insulin increased glucose uptake significantly and to the same degree in the muscles examined. Insulin + contraction increased glucose uptake above that of insulin or contraction alone, but this effect was only statistically significant in the soleus, plantaris and white gastrocnemius. The combined effects of insulin + contraction of glucose uptake were not fully additive in any of the muscles investigated. These results suggest that (1) insulin and muscle contraction are mobilizing two separate pools of GLUT-4 protein, and (2) the increase in skeletal-muscle glucose uptake due to insulin + contraction is not due to an increase in plasma-membrane GLUT-4 protein concentration above that observed for insulin or contraction alone.
Collapse
Affiliation(s)
- J T Brozinick
- Department of Kinesiology, University of Texas, Austin 78712
| | | | | | | |
Collapse
|
|
42
|
Gould GW, Holman GD. The glucose transporter family: structure, function and tissue-specific expression. Biochem J 1993; 295 ( Pt 2):329-41. [PMID: 8240230 PMCID: PMC1134886 DOI: 10.1042/bj2950329] [Citation(s) in RCA: 544] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Affiliation(s)
- G W Gould
- Department of Biochemistry, University of Glasgow, Scotland, U.K
| | | |
Collapse
|
|
43
|
Cleland PJ, Abel KC, Rattigan S, Clark MG. Long-term treatment of isolated rat soleus muscle with phorbol ester leads to loss of contraction-induced glucose transport. Biochem J 1990; 267:659-63. [PMID: 2187433 PMCID: PMC1131348 DOI: 10.1042/bj2670659] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Muscle contraction involves mobilization of intracellular Ca2+ and is associated with several metabolic adjustments, including increased glucose transport. In the present study isolated rat soleus muscles were exposed to 12-O-tetradecanoylphorbol 13-acetate, and responses to both insulin and contraction in terms of glucose transport were assessed. Muscles treated with this phorbol ester for 12 h showed an increased basal rate of 3-O-methylglucose uptake, and responded partially to insulin but did not respond to contraction. Phorbol-ester-treated and non-treated (vehicle-only) muscles were indistinguishable in terms of pre-contraction content of adenine nucleotide, phosphocreatine, lactate and glycogen, as well as contractile performance and contraction-induced glycogenolysis. Phorbol ester treatment of isolated solei for 12 h resulted in the loss of 90% of protein kinase C activity as determined with histone IIIs as substrate, and 70% as determined by using phorbol ester binding. It is concluded that treatment of solei with phorbol ester gives rise to a marked loss of contraction-induced glucose transport.
Collapse
Affiliation(s)
- P J Cleland
- Department of Biochemistry, University of Tasmania, Hobart, Australia
| | | | | | | |
Collapse
|
|
44
|
Wasserman DH, Abumrad NN. Physiological bases for the treatment of the physically active individual with diabetes. Sports Med 1989; 7:376-92. [PMID: 2662324 DOI: 10.2165/00007256-198907060-00003] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Substrate utilisation and glucose homoeostasis during exercise is controlled by the effects of precise changes in insulin, glucagon and the catecholamines. The important role these hormones play is clearly seen in people with diabetes, as the normal endocrine response is often lost. In individuals with insulin-dependent diabetes (IDDM), there can be an increased risk of hypoglycaemia during or after exercise or, conversely, there can be a worsening of the diabetic state if insulin deficiency is present. In contrast, it appears that people with non-insulin-dependent diabetes (NIDDM) can generally exercise without fear of a deleterious metabolic response. The exercise response both in healthy subjects and in those with diabetes is dependent on many factors such as age, nutritional status and the duration and intensity of exercise. Since there are so many variables which govern individual response to exercise, an exact exercise prescription for all people with diabetes cannot be made. There are many adjustments to the therapeutic regimen which an individual with IDDM can make in order to avoid hypoglycaemia during or after exercise. In general, a reduction in insulin dosage and the added ingestion and continual availability of carbohydrates are wise precautions. On the other hand, exercise should be postponed if blood glucose is greater than 2500 mg/L and ketones are present in the urine. As more is understood about the regulation of substrate metabolism during exercise, more refined therapeutic strategies can be defined. An understanding of the metabolic response to exercise is critical for generating an effective and safe training programme for all diabetic individuals who wish to be physically active.
Collapse
Affiliation(s)
- D H Wasserman
- Departments of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee
| | | |
Collapse
|
|
45
|
Wu GY, Thompson JR. The effect of ketone bodies on alanine and glutamine metabolism in isolated skeletal muscle from the fasted chick. Biochem J 1988; 255:139-44. [PMID: 2904261 PMCID: PMC1135201 DOI: 10.1042/bj2550139] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
The effects of ketone bodies on the metabolism of alanine and glutamine were studied in isolated extensor digitorum communis (EDC) muscles from 24 h-fasted chicks. (1) Acetoacetate and DL-beta-hydroxybutyrate (4 mM) markedly inhibit branched-chain amino acid (BCAA) transamination and alanine formation. (2) Ketone bodies (1 and 4 mM) increase the intracellular concentration and release of glutamate and glutamine, suggesting that inhibition of BCAA transamination does not limit intracellular availability of glutamate for alanine synthesis. (3) Ketone bodies (1 and 4 mM) do not affect glucose uptake by muscles, but decrease the rate of glycolysis as well as the intracellular concentration and release of pyruvate in muscles. (4) Addition of 12 mM-glucose increases the formation of alanine in muscles incubated in the absence of ketone bodies, but has no effect in muscles incubated in the presence of 4 mM ketone bodies. (5) Addition of 5 mM-pyruvate to the media prevents the inhibiting effect of ketone bodies on BCAA transamination and alanine synthesis. These results suggest that ketone bodies decrease alanine synthesis by limiting the intracellular availability of pyruvate, owing to inhibition of glycolysis, and inhibit BCAA transamination by decreasing the intracellular concentration of amino-group acceptors such as pyruvate in EDC muscles from fasted chicks.
Collapse
Affiliation(s)
- G Y Wu
- Department of Animal Science, University of Alberta, Edmonton, Canada
| | | |
Collapse
|