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Malvandi AM, Gerosa L, Banfi G, Lombardi G. The bone-muscle unit: from mechanical coupling to soluble factors-mediated signaling. Mol Aspects Med 2025; 103:101367. [PMID: 40339487 DOI: 10.1016/j.mam.2025.101367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2025] [Revised: 04/18/2025] [Accepted: 04/29/2025] [Indexed: 05/10/2025]
Abstract
Skeletal muscles (SKM) and bones form a morpho-functional unit, interconnected throughout life primarily through biomechanical coupling. This relationship serves as a key reciprocal stimulus, but they also interact via various hormones, such as sex steroids, growth hormone-insulin-like growth factor 1 (GH-IGF1) axis hormones, and adipokines like leptin and adiponectin. Additionally, myokines (released by muscles) and osteokines (released by bones) facilitate dense crosstalk, influencing each other's activity. Key myokines include interleukin (IL)-6, IL-7, IL-15, and myostatin, while osteocalcin (OC) and sclerostin are crucial bone-derived mediators affecting SKM cells. Moreover, miRNAs act as endocrine-like regulators, contributing to a complex network. This review covers the current understanding of bone-muscle crosstalk, which is essential for grasping the musculoskeletal apparatus's role in disease pathogenesis and may inform therapeutic development.
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Affiliation(s)
- Amir Mohammad Malvandi
- Laboratory of Experimental Biochemistry & Advanced Diagnostics, IRCCS Ospedale Galeazzi-Sant'Ambrogio, Milan, Italy
| | - Laura Gerosa
- Laboratory of Experimental Biochemistry & Advanced Diagnostics, IRCCS Ospedale Galeazzi-Sant'Ambrogio, Milan, Italy
| | - Giuseppe Banfi
- Laboratory of Experimental Biochemistry & Advanced Diagnostics, IRCCS Ospedale Galeazzi-Sant'Ambrogio, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy
| | - Giovanni Lombardi
- Laboratory of Experimental Biochemistry & Advanced Diagnostics, IRCCS Ospedale Galeazzi-Sant'Ambrogio, Milan, Italy; Department of Athletics, Strength and Conditioning, Poznań University of Physical Education, Poznań, Poland.
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Sansoni V, Lombardi G, Díaz-Garzón J, Calle PF, Bartlett WA, Coşkun A, Itkonen O, Jonker N, Sandberg S, Aarsand AK, Banfi G, Carobene A. Novel biomarkers in bone pathophysiology: Establishing reference intervals and biological variations estimates for serum leptin, sclerostin, lipocalin-2, osteoprotegerin, resistin and Dickkopf-related protein-1 from the European biological variation study (EuBIVAS) populations. Clin Chim Acta 2025; 570:120213. [PMID: 40010661 DOI: 10.1016/j.cca.2025.120213] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2025] [Accepted: 02/21/2025] [Indexed: 02/28/2025]
Abstract
A range of biomarkers of bone metabolism are thought to mediate adipose tissue-bone crosstalk and fulfil a homeostatic role. While considered clinically relevant, their utility and application appears limited by lack of data characterising biological variability and reference intervals rather than by analytical issues. We have therefore studied the biological variation (BV) of these biomarkers. Concentrations of Dikkopf-related protein 1, leptin, osteoprotegerin, sclerostin, lipocalin2 (Lcn2) and resistin were measured by Luminex assays in serum samples from the EuBIVAS study. Samples were taken once per week, over 10 consecutive weeks, from 91 subjects in cohorts from 5 European countries. Estimates of analytical variation (CVA), within-subject (CVI) and between-subject (CVG) BV were calculated and analytical imprecision (CVAPS) and analytical bias (BAPS) specifications, index of individuality (II), reference change values (RCV) for increase and decrease and the number of samples required to estimate the homeostatic set points (NHSPs) were derived. Mean concentrations differed between males and females for leptin, osteoprotegerin, and sclerostin, and for osteoprotegerin and sclerostin between females in fertile and menopausal ages. No male-to-female differences were observed in CVI estimates. Index of individuality was below 0.6, for all measurands. Determination of reference intervals (RI) limits indicated that all, with the exception Lcn2, described data which were non-gaussian distributed and that only leptin differed between sexes. Availability of high-quality biological variation enables objective assessment of the bone metabolism biomarker results which may enhance their clinical utility. The data indicates that they exhibit significant individuality.
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Affiliation(s)
- Veronica Sansoni
- Laboratory of Experimental Biochemistry and Advanced Diagnostics, IRCCS Ospedale Galeazzi-Sant'Ambrogio, Milan, Italy
| | - Giovanni Lombardi
- Laboratory of Experimental Biochemistry and Advanced Diagnostics, IRCCS Ospedale Galeazzi-Sant'Ambrogio, Milan, Italy; Department of Athletics, Strength and Conditioning, Poznań University of Physical Education, Poznań, Poland.
| | - Jorge Díaz-Garzón
- Department of Laboratory Medicine. Hospital Universitario La Paz, Madrid, Spain
| | | | - William A Bartlett
- School of Science and Engineering, University of Dundee, Dundee, Scotland, UK
| | - Abdurrahman Coşkun
- Acibadem Mehmet Ali Aydınlar University, School of Medicine, Atasehir, Istanbul, Turkey
| | - Outi Itkonen
- HUS Diagnostic Center, Helsinki University Hospital and University of Helsinki, Finland
| | - Niels Jonker
- Certe, Wilhelmina Ziekenhuis Assen, Assen, the Netherlands
| | - Sverre Sandberg
- Department of Medical Biochemistry and Pharmacology, Haukeland University Hospital, Bergen, Norway; Norwegian Organization for Quality Improvement of Laboratory Examinations (Noklus), Haraldsplass Deaconess Hospital, Bergen, Norway; Department of Global Health and Primary Care, Faculty of Medicine, University of Bergen, Norway
| | - Aasne K Aarsand
- Department of Medical Biochemistry and Pharmacology, Haukeland University Hospital, Bergen, Norway; Norwegian Organization for Quality Improvement of Laboratory Examinations (Noklus), Haraldsplass Deaconess Hospital, Bergen, Norway
| | - Giuseppe Banfi
- Laboratory of Experimental Biochemistry and Advanced Diagnostics, IRCCS Ospedale Galeazzi-Sant'Ambrogio, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy
| | - Anna Carobene
- Laboratory Medicine, IRCCS San Raffaele Scientific Institute, Milan, Italy
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Sasimontonkul S, Sirivarasai J. The 40-min HIIT acutely induced bone formation which was likely through the increases in muscle derived interleukin 6 and adiponectin activation: The 16 weeks of HIIT intervention, longitudinal randomized controlled trial. Bone 2024; 184:117105. [PMID: 38636620 DOI: 10.1016/j.bone.2024.117105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 04/01/2024] [Accepted: 04/15/2024] [Indexed: 04/20/2024]
Abstract
PURPOSE There is some controversy regarding cytokines released from adipocytes, particularly adiponectin, leptin, and IL6 that regulate bone remodeling. In addition, IL6 is released from muscle contraction, which might have a distinct role in bone remodeling. Hence, this study investigated whether muscle contraction during a session of 40 min of high intensity interval training (40-min HIIT) and after 16 weeks of HIIT (16-wk HIIT) altered the release of those cytokines and bone remodeling in overweight women. METHODS In total, 22 overweight, premenopausal women were randomly assigned to either the exercise or the control group. The exercise participants engaged in the 40-min HIIT session at 80-90 % of their heart rate reserve (HRR) three times weekly for 16 weeks, while the control participants performed their routine daily activities. Blood was drawn after overnight fasting and immediately after completing the 40-min HIIT sessions to investigate the association of adiponectin, leptin, IL6, CTX, and P1NP through the acute effect of the 40-min HIIT sessions. This process was repeated after the 16-wk intervention program to observe the training effect of HIIT on cytokines linkage. The bone mineral density (BMD) levels of the distal tibia, femur, and lumbar spine were determined prior to and after the 16-wk intervention using dual-energy X-ray absorptiometry. RESULTS The P1NP level increased by 8.29-20.52 % (95 % CI) and by 2.91-15.54 % after completing the first and last bouts of the 40-min HIIT sessions, respectively. In addition, IL6 increased by 13.39-28.03 % (95 % CI), while serum CTX and adiponectin were unaltered from the acute effect of the 40-min HIIT sessions. There was an association between the increases in P1NP and adiponectin (r = 0.682, p = 0.015); however, the increase in P1NP was mostly associated with the increase in IL6 (r = 0.572, p = 0.054) after completing a 40-min HIIT session. After the 16-wk HIIT program, the resting adiponectin level of the exercise participants increased; however, this was associated with neither bone biomarkers nor BMD. The BMDs of the exercise participants were maintained; however, the tibial BMD of the control participants decreased with an increase in the resting CTX level after 16 weeks. CONCLUSION Muscle contraction during the 40-min HIIT session elevated the IL6 level, which might have subsequently enhanced bone formation. Furthermore, the association between acute changes in adiponectin and P1NP suggested the possibility of an increase in the sensitivity of the adiponectin receptor in osteoblasts.
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Affiliation(s)
- Siriporn Sasimontonkul
- Department of Rehabilitation and Movement Sciences, Faculty of Sports Science, Kasetsart University, Bangkok, Thailand.
| | - Jintana Sirivarasai
- Graduate Program in Nutrition, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
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Stunes AK, Brobakken CL, Sujan MAJ, Aagård N, Brevig MS, Wang E, Syversen U, Mosti MP. Acute Effects of Strength and Endurance Training on Bone Turnover Markers in Young Adults and Elderly Men. Front Endocrinol (Lausanne) 2022; 13:915241. [PMID: 35846315 PMCID: PMC9279869 DOI: 10.3389/fendo.2022.915241] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Accepted: 05/30/2022] [Indexed: 11/13/2022] Open
Abstract
CONTEXT Exercise is recognized as an important strategy to prevent bone loss, but its acute effects on bone turnover markers (BTMs) and related markers remain uncertain. OBJECTIVE To assess the acute effects of two different exercise modes on BTMs and related markers in young adults of both sexes and elderly men. DESIGN SETTING PARTICIPANTS This was a three-group crossover within-subjects design study with a total of 53 participants-19 young women (aged 22-30), 20 young men (aged 21-30 years), and 14 elderly men (aged 63-74 years)-performing two different exercise sessions [strength training (ST) and high-intensity interval training (HIIT)] separated by 2 weeks, in a supervised laboratory setting. MAIN OUTCOME MEASURES Plasma volume-corrected serum measurements of the BTMs C-terminal telopeptide of type 1 collagen (CTX-I) and procollagen of type 1 N-terminal propeptide (P1NP), total osteocalcin (OC), sclerostin, and lipocalin-2 (LCN2) at baseline, immediately after, and 3 and 24 h after each of the two exercise modes were performed. RESULTS AND CONCLUSION Analyses revealed sex- and age-dependent differences in BTMs and related bone markers at baseline and time-, sex-, and age-dependent differences in response to exercise. No differences between exercise modes were observed for BTM response except for sclerostin in young men and LCN2 in elderly men. An acute, transient, and uniform increase in P1NP/CTX-1 ratio was found in young participants, demonstrating that beneficial skeletal effects on bone metabolism can be attained through both aerobic endurance and resistance exercise, although this effect seems to be attenuated with age. The acute effects of exercise on bone-related biomarkers were generally blunted after 24 h, suggesting that persistent alterations following prolonged exercise interventions should be assessed at later time points.
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Affiliation(s)
- Astrid Kamilla Stunes
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway
- Medical Clinic, St. Olavs University Hospital, Trondheim, Norway
- *Correspondence: Astrid Kamilla Stunes, orcid.org/0000-0003-1074-5199
| | - Cathrine Langlie Brobakken
- Department of Circulation and Medical Imaging, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway
- Myworkout, Medical Rehabilitation Clinic, Trondheim, Norway
| | - Md Abu Jafar Sujan
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway
| | - Norun Aagård
- Department of Circulation and Medical Imaging, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway
- Myworkout, Medical Rehabilitation Clinic, Trondheim, Norway
| | - Martin Siksjø Brevig
- Department of Circulation and Medical Imaging, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway
| | - Eivind Wang
- Faculty of Health and Social Sciences, Molde University College, Molde, Norway
- Department of Psychosis and Rehabilitation, Psychiatry Clinic, St. Olavs University Hospital, Trondheim, Norway
| | - Unni Syversen
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway
- Department of Endocrinology, St. Olavs University Hospital, Trondheim, Norway
| | - Mats Peder Mosti
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway
- Medical Clinic, St. Olavs University Hospital, Trondheim, Norway
- Department of Research and Development, Clinic of Substance Use and Addiction Medicine, St. Olavs University Hospital, Trondheim, Norway
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Lombardi G, Berjano P, Cecchinato R, Langella F, Perego S, Sansoni V, Tartara F, Regazzoni P, Lamartina C. Peri-Surgical Inflammatory Profile Associated with Mini-Invasive or Standard Open Lumbar Interbody Fusion Approaches. J Clin Med 2021; 10:jcm10143128. [PMID: 34300294 PMCID: PMC8303236 DOI: 10.3390/jcm10143128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 06/06/2021] [Accepted: 07/13/2021] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Different surgical approaches are available for lumbar interbody fusion (LIF) to treat disc degeneration. However, a quantification of their invasiveness is lacking, and the definition of minimally invasive surgery (MIS) has not been biochemically detailed. We aimed at characterizing the inflammatory, hematological, and clinical peri-surgical responses to different LIF techniques. METHODS 68 healthy subjects affected by single-level discopathy (L3 to S1) were addressed to MIS, anterior (ALIF, n = 21) or lateral (LLIF, n = 23), and conventional approaches, transforaminal (TLIF, n = 24), based on the preoperative clinical assessment. Venous blood samples were taken 24 h before the surgery and 24 and 72 h after surgery to assess a wide panel of inflammatory and hematological markers. RESULTS martial (serum iron and transferrin) and pro-angiogenic profiles (MMP-2, TWEAK) were improved in ALIF and LLIF compared to TLIF, while the acute phase response (C-reactive protein, sCD163) was enhanced in LLIF. CONCLUSIONS MIS procedures (ALIF and LLIF) associated with a reduced incidence of post-operative anemic status, faster recovery, and enhanced pro-angiogenic stimuli compared with TLIF. LLIF associated with an earlier activation of innate immune mechanisms than ALIF and TLIF. The trend of the inflammation markers confirms that the theoretically defined mini-invasive procedures behave as such.
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Affiliation(s)
- Giovanni Lombardi
- Laboratory of Experimental Biochemistry and Molecular Biology, IRCCS Istituto Ortopedico Galeazzi, 20161 Milan, Italy; (G.L.); (S.P.); (V.S.)
- Department of Athletics, Strength and Conditioning, Poznań University of Physical Education and Sport, 61-871 Poznań, Poland
| | - Pedro Berjano
- OU GSpine 4, IRCCS Istituto Ortopedico Galeazzi, 20161 Milan, Italy; (P.B.); (R.C.); (C.L.)
| | - Riccardo Cecchinato
- OU GSpine 4, IRCCS Istituto Ortopedico Galeazzi, 20161 Milan, Italy; (P.B.); (R.C.); (C.L.)
| | - Francesco Langella
- OU GSpine 4, IRCCS Istituto Ortopedico Galeazzi, 20161 Milan, Italy; (P.B.); (R.C.); (C.L.)
- Correspondence:
| | - Silvia Perego
- Laboratory of Experimental Biochemistry and Molecular Biology, IRCCS Istituto Ortopedico Galeazzi, 20161 Milan, Italy; (G.L.); (S.P.); (V.S.)
| | - Veronica Sansoni
- Laboratory of Experimental Biochemistry and Molecular Biology, IRCCS Istituto Ortopedico Galeazzi, 20161 Milan, Italy; (G.L.); (S.P.); (V.S.)
| | - Fulvio Tartara
- IRCCS Istituto Neurologico Nazionale C. Mondino, 27100 Pavia, Italy;
| | - Pietro Regazzoni
- Department of Trauma Surgery, University Hospital Basel, 4031 Basel, Switzerland;
| | - Claudio Lamartina
- OU GSpine 4, IRCCS Istituto Ortopedico Galeazzi, 20161 Milan, Italy; (P.B.); (R.C.); (C.L.)
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Brunetti G, D'Amato G, De Santis S, Grano M, Faienza MF. Mechanisms of altered bone remodeling in children with type 1 diabetes. World J Diabetes 2021; 12:997-1009. [PMID: 34326950 PMCID: PMC8311475 DOI: 10.4239/wjd.v12.i7.997] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 03/17/2021] [Accepted: 05/22/2021] [Indexed: 02/06/2023] Open
Abstract
Bone loss associated with type 1 diabetes mellitus (T1DM) begins at the onset of the disease, already in childhood, determining a lower bone mass peak and hence a greater risk of osteoporosis and fractures later in life. The mechanisms underlying diabetic bone fragility are not yet completely understood. Hyperglycemia and insulin deficiency can affect the bone cells functions, as well as the bone marrow fat, thus impairing the bone strength, geometry, and microarchitecture. Several factors, like insulin and growth hormone/insulin-like growth factor 1, can control bone marrow mesenchymal stem cell commitment, and the receptor activator of nuclear factor-κB ligand/osteoprotegerin and Wnt-b catenin pathways can impair bone turnover. Some myokines may have a key role in regulating metabolic control and improving bone mass in T1DM subjects. The aim of this review is to provide an overview of the current knowledge of the mechanisms underlying altered bone remodeling in children affected by T1DM.
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Affiliation(s)
- Giacomina Brunetti
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University "A. Moro" of Bari, Bari 70125, Italy
| | - Gabriele D'Amato
- Department of Women’s and Children’s Health, ASL Bari, Neonatal Intensive Care Unit, Di Venere Hospital, Bari 70124, Italy
| | - Stefania De Santis
- Department of Pharmacy-Drug Science, University of Bari Aldo Moro, Bari 70126, Italy
| | - Maria Grano
- Department of Emergency and Organ Transplantation, Univ Bari, Bari 70124, Italy
| | - Maria Felicia Faienza
- Department of Biomedical Sciences and Human Oncology, Pediatric Unit, University "A.Moro", Bari 70124, Italy
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Vitale JA, Sansoni V, Faraldi M, Messina C, Verdelli C, Lombardi G, Corbetta S. Circulating Carboxylated Osteocalcin Correlates With Skeletal Muscle Mass and Risk of Fall in Postmenopausal Osteoporotic Women. Front Endocrinol (Lausanne) 2021; 12:669704. [PMID: 34025583 PMCID: PMC8133362 DOI: 10.3389/fendo.2021.669704] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Accepted: 04/12/2021] [Indexed: 12/31/2022] Open
Abstract
Background Bone and skeletal muscle represent a single functional unit. We cross-sectionally investigated body composition, risk of fall and circulating osteocalcin (OC) isoforms in osteoporotic postmenopausal women to test the hypothesis of an involvement of OC in the bone-muscle crosstalk. Materials and Methods Twenty-nine non-diabetic, non-obese, postmenopausal osteoporotic women (age 72.4 ± 6.8 years; BMI 23.0 ± 3.3 kg/m2) underwent to: 1) fasting blood sampling for biochemical and hormone assays, including carboxylated (cOC) and uncarboxylated (uOC) osteocalcin; 2) whole-body dual energy X-ray absorptiometry (DXA) to assess total and regional body composition; 3) magnetic resonance imaging to determine cross-sectional muscle area (CSA) and intermuscular adipose tissue (IMAT) of thigh muscles; 4) risk of fall assessment through the OAK system. Results Appendicular skeletal muscle index (ASMMI) was low in 45% of patients. Forty percent got a low OAK score, consistent with moderate-severe risk of fall, which was predicted by low legs lean mass and increased total fat mass. Circulating cOC levels showed significantly correlated with βCTx-I, lean mass parameters including IMAT, and OAK score. Fractured and unfractured women did not differ for any of the analyzed parameters, though cOC and uOC positively correlated with legs lean mass, OAK score and bone markers only in fractured women. Conclusions Data supported the relationship between OC and skeletal muscle mass and function in postmenopausal osteoporotic women. Serum cOC, but not uOC, emerges as mediator in the bone-muscle crosstalk. Circulating cOC and uOC levels may be differentially regulated in fractured and unfractured osteoporotic women, suggesting underlying differences in bone metabolism.
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Affiliation(s)
- Jacopo Antonino Vitale
- Laboratory of Movement and Sport Science, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy
| | - Veronica Sansoni
- Laboratory of Experimental Biochemistry and Molecular Biology, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy
| | - Martina Faraldi
- Laboratory of Experimental Biochemistry and Molecular Biology, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy
| | - Carmelo Messina
- Radiology Unit, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy
- Department of Biomedical Sciences for Health, University of Milan, Milan, Italy
| | - Chiara Verdelli
- Laboratory of Experimental Endocrinology, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy
| | - Giovanni Lombardi
- Laboratory of Experimental Biochemistry and Molecular Biology, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy
- Department of Athletics, Strength and Conditioning, Poznań University of Physical Education, Poznań, Poland
| | - Sabrina Corbetta
- Endocrinology and Diabetology Service, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy
- Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy
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Faraldi M, Gerosa L, Gomarasca M, Sansoni V, Perego S, Ziemann E, Banfi G, Lombardi G. A Physically Active Status Affects the Circulating Profile of Cancer-Associated miRNAs. Diagnostics (Basel) 2021; 11:diagnostics11050820. [PMID: 33946605 PMCID: PMC8147229 DOI: 10.3390/diagnostics11050820] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 04/22/2021] [Accepted: 04/29/2021] [Indexed: 02/06/2023] Open
Abstract
Circulating miRNAs are ideal diagnostics and prognostics biomarkers in cancer since altered levels of specific miRNAs have been associated to development/progression of several cancers. Physical activity is a recognized preventive strategy against several cancers, but it may also modify the baseline levels of cancer-associated miRNAs and, hence, may act as a confounding pre-analytical variable. This study aimed at understanding whether physical activity-dependent changes in cancer-associated circulating miRNAs profile could act as a confounding variable. A panel comprising 179 miRNAs was assayed in plasma from 20 highly trained and 10 sedentary men. RT-qPCR data were analyzed with the 2−2ΔΔCT methods and normalized on hsa-miR-320d, as determined by bioinformatics analysis. miRNAs associated with the diagnosis of the most prevalent cancers were considered. Only those miRNAs, relevantly associated with cancers, found ≥2-fold up- or downregulated in highly trained subjects compared to sedentary were disclosed. The results reveal that chronic physical activity determined modifications altering the baseline level of several cancer-associated miRNAs and, hence, their diagnostic and prognostic potential. In conclusion, based on our results, a physically active status emerges as an important pre-analytical variable able to alter the basal level of circulating miRNAs, and these alterations might be considered as potentially misleading the analytical output.
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Affiliation(s)
- Martina Faraldi
- Laboratory of Experimental Biochemistry & Molecular Biology, IRCCS Istituto Ortopedico Galeazzi, 20161 Milano, Italy; (M.F.); (M.G.); (V.S.); (S.P.); (G.B.); (G.L.)
| | - Laura Gerosa
- Gruppo San Donato Foundation, 20122 Milano, Italy
- Correspondence: ; Tel.: +39-02166214068
| | - Marta Gomarasca
- Laboratory of Experimental Biochemistry & Molecular Biology, IRCCS Istituto Ortopedico Galeazzi, 20161 Milano, Italy; (M.F.); (M.G.); (V.S.); (S.P.); (G.B.); (G.L.)
| | - Veronica Sansoni
- Laboratory of Experimental Biochemistry & Molecular Biology, IRCCS Istituto Ortopedico Galeazzi, 20161 Milano, Italy; (M.F.); (M.G.); (V.S.); (S.P.); (G.B.); (G.L.)
| | - Silvia Perego
- Laboratory of Experimental Biochemistry & Molecular Biology, IRCCS Istituto Ortopedico Galeazzi, 20161 Milano, Italy; (M.F.); (M.G.); (V.S.); (S.P.); (G.B.); (G.L.)
| | - Ewa Ziemann
- Department of Athletics, Strength and Conditioning, Poznań University of Physical Education, 61-871 Poznań, Poland;
| | - Giuseppe Banfi
- Laboratory of Experimental Biochemistry & Molecular Biology, IRCCS Istituto Ortopedico Galeazzi, 20161 Milano, Italy; (M.F.); (M.G.); (V.S.); (S.P.); (G.B.); (G.L.)
- Vita-Salute San Raffaele University, 20132 Milano, Italy
| | - Giovanni Lombardi
- Laboratory of Experimental Biochemistry & Molecular Biology, IRCCS Istituto Ortopedico Galeazzi, 20161 Milano, Italy; (M.F.); (M.G.); (V.S.); (S.P.); (G.B.); (G.L.)
- Department of Athletics, Strength and Conditioning, Poznań University of Physical Education, 61-871 Poznań, Poland;
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Gerosa L, Lombardi G. Bone-to-Brain: A Round Trip in the Adaptation to Mechanical Stimuli. Front Physiol 2021; 12:623893. [PMID: 33995117 PMCID: PMC8120436 DOI: 10.3389/fphys.2021.623893] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 04/06/2021] [Indexed: 12/12/2022] Open
Abstract
Besides the classical ones (support/protection, hematopoiesis, storage for calcium, and phosphate) multiple roles emerged for bone tissue, definitively making it an organ. Particularly, the endocrine function, and in more general terms, the capability to sense and integrate different stimuli and to send signals to other tissues, has highlighted the importance of bone in homeostasis. Bone is highly innervated and hosts all nervous system branches; bone cells are sensitive to most of neurotransmitters, neuropeptides, and neurohormones that directly affect their metabolic activity and sensitivity to mechanical stimuli. Indeed, bone is the principal mechanosensitive organ. Thanks to the mechanosensing resident cells, and particularly osteocytes, mechanical stimulation induces metabolic responses in bone forming (osteoblasts) and bone resorbing (osteoclasts) cells that allow the adaptation of the affected bony segment to the changing environment. Once stimulated, bone cells express and secrete, or liberate from the entrapping matrix, several mediators (osteokines) that induce responses on distant targets. Brain is a target of some of these mediator [e.g., osteocalcin, lipocalin2, sclerostin, Dickkopf-related protein 1 (Dkk1), and fibroblast growth factor 23], as most of them can cross the blood-brain barrier. For others, a role in brain has been hypothesized, but not yet demonstrated. As exercise effectively modifies the release and the circulating levels of these osteokines, it has been hypothesized that some of the beneficial effects of exercise on brain functions may be associated to such a bone-to-brain communication. This hypothesis hides an interesting clinical clue: may well-addressed physical activities support the treatment of neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases?
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Affiliation(s)
| | - Giovanni Lombardi
- Laboratory of Experimental Biochemistry & Molecular Biology, IRCCS Istituto Ortopedico Galeazzi, Milano, Italy.,Department of Athletics, Strength and Conditioning, Poznań University of Physical Education, Poznań, Poland
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Beneficial effects of whole-body cryotherapy on glucose homeostasis and amino acid profile are associated with a reduced myostatin serum concentration. Sci Rep 2021; 11:7097. [PMID: 33782504 PMCID: PMC8007810 DOI: 10.1038/s41598-021-86430-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Accepted: 03/16/2021] [Indexed: 01/12/2023] Open
Abstract
The study investigated the effect of single and chronic (10 sessions) whole-body cryotherapy (WBC; 3-min, − 110 °C) on amino acid (AA) profile, myostatin, fibroblast growth factor 21 (FGF21), and concentrations of brain-derived neurotrophic factor (BDNF), irisin and adiponectin in relation to glucose homeostasis. Thirty-five, healthy men were randomly split into experimental (young: 28 ± 7 years and middle-aged: 51 ± 3 years) and control groups. Blood samples were taken before and 1 h after the first and last (10th) WBC session. Baseline myostatin correlated significantly with visceral fat area, glucose, insulin, HOMA-IR and irisin (all p < 0.05). The single session of WBC induced temporary changes in AA profile, whereas chronic exposure lowered valine and asparagine concentrations (p < 0.01 and p = 0.01, respectively) compared to the baseline. The chronic WBC reduced fasting glucose (p = 0.04), FGF21 (− 35.8%, p = 0.06) and myostatin (-18.2%, p = 0.06). Still, the effects were age-dependent. The decrease of myostatin was more pronounced in middle-aged participants (p < 0.01). Concentrations of irisin and adiponectin increased in response to chronic WBC, while BDNF level remained unchanged. By improving the adipo-myokine profile, chronic WBC may reduce effectively the risk of the metabolic syndrome associated with hyperinsulinemia, increased levels of valine and asparagine, and muscle atrophy.
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Jaworska J, Laskowski R, Ziemann E, Zuczek K, Lombardi G, Antosiewicz J, Zurek P. The Specific Judo Training Program Combined With the Whole Body Cryostimulation Induced an Increase of Serum Concentrations of Growth Factors and Changes in Amino Acid Profile in Professional Judokas. Front Physiol 2021; 12:627657. [PMID: 33633589 PMCID: PMC7900507 DOI: 10.3389/fphys.2021.627657] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Accepted: 01/18/2021] [Indexed: 01/17/2023] Open
Abstract
This study aimed to evaluate the effect of a specific training program, supported by 10 sessions of whole body cryostimulation, on growth factors concentrations, amino acids profile and motor abilities in professional judokas. Ultimately, twelve athletes took part in the study. They were randomly assigned to the cryostimulation group (CRY, n = 6) or the control group (CON, n = 6). During 2 weeks of the judo training program, the CRY group performed 10 cryo-sessions (3-min, at a temperature of -110°C) and the CON group rested passively. Anthropometric measurements, a strength test, the Special Judo Efficiency Test (SJET) were assessed 2 days before and after the judo training program. Blood samples were collected at rest, 1 h after the first and the second SJET and 1 h after the first and the last cryo-session to establish growth factors and amino acid concentrations. Lactate level was measured before, immediately after and 1 h after the first and the second SJET. The applied intervention resulted in a significant increase of resting concentrations of brain-derived neurotrophic factor (from 10.23 ± 1.61 to 15.13 ± 2.93 ng⋅ml-1; p = 0.01) and insulin-like growth factor 1 (IGF-1; from 174.29 ± 49.34 to 300.50 ± 43.80 pg⋅ml-1; p = 0.00) in the CRY group. A different response was registered 1 h directly post SJET in the CRY group (a significant increase of IGF-1, interleukin 15 and irisin: p = 0.01; p = 0.00; p = 0.03). Additionally, the significant drop of proline and leucine concentrations in the CRY group was obtained. Athletes' performance remained unchanged in both groups. However, subjects perceived positive changes induced by the intervention - not directly after cryostimulation but in response to the specific training workload. The increase of growth factors concentrations and the improvement of amino acid profile (proline and leucine) contributed to maintaining a high level of muscle function.
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Affiliation(s)
- Joanna Jaworska
- Department of Physical Education and Lifelong Sports, Poznań University of Physical Education, Poznań, Poland
| | - Radoslaw Laskowski
- Department of Physiology and Biochemistry, Gdańsk University of Physical Education and Sport, Gdańsk, Poland
| | - Ewa Ziemann
- Department of Athletics, Strength and Conditioning, Poznań University of Physical Education, Poznań, Poland
| | - Klaudia Zuczek
- Department of Medical Biology and Genetics, Faculty of Biology, University of Gdańsk, Gdańsk, Poland
| | - Giovanni Lombardi
- Department of Athletics, Strength and Conditioning, Poznań University of Physical Education, Poznań, Poland.,IRCCS Galeazzi Orthopaedic Institute, Lab Experimental Biochemistry & Molecular Biology, Milan, Italy
| | - Jedrzej Antosiewicz
- Department of Bioenergetics and Physiology of Exercise, Medical University of Gdańsk, Gdańsk, Poland
| | - Piotr Zurek
- Department of Physical Culture Gorzow Wielkopolski, Poznań University of Physical Education, Poznań, Poland
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Faraldi M, Gomarasca M, Perego S, Sansoni V, Banfi G, Lombardi G. Effect of collection matrix, platelet depletion, and storage conditions on plasma extracellular vesicles and extracellular vesicle-associated miRNAs measurements. Clin Chem Lab Med 2020; 59:893-903. [PMID: 33555147 DOI: 10.1515/cclm-2020-1296] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Accepted: 11/17/2020] [Indexed: 12/20/2022]
Abstract
OBJECTIVES The interest around circulating extracellular vesicles and their cargo in diagnostics has greatly increased; however, several pre-analytical variables affect their determination. In this study, we investigated the effects of sample matrix, processing, and plasma storage delay and temperature on extracellular vesicles and their miRNA content. METHODS Blood was collected from 10 male volunteers in dipotassium ethylendiaminotetraacetate-coated tubes (K2EDTA), either with plasma-preparation tube (PPT) or without (K2E) gel separator. A stepwise centrifugation was applied to K2E aliquots to obtain platelet-poor plasma (PPP). K2E, PPP and PPT plasma, stored under different conditions, were assayed for extracellular vesicles concentration and size distribution, through dynamic laser light scattering, and microRNAs content, by qPCR. RESULTS PPP samples were characterized by the lowest extracellular vesicles count and miRNA detectability. Although having no effects on extracellular vesicles total concentration, storage conditions influenced microRNAs detectability, mainly in PPP and PPT samples. Extracellular vesicles-associated miRNAs levels in K2E were, in general, higher than in PPP and to a very limited extent to PPT. Storage temperature and delay did not affect their profile in K2E samples. CONCLUSIONS Extracellular vesicles count and extracellular vesicles miRNA profile changed under the analyzed pre-analytical variables, showing the greatest stability in K2E samples. Since pre-analytical variables differently affected extracellular vesicles and their miRNA content, they should be considered in each experimental setting and clinical routine.
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Affiliation(s)
- Martina Faraldi
- Laboratory of Experimental Biochemistry & Molecular Biology, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy
| | - Marta Gomarasca
- Laboratory of Experimental Biochemistry & Molecular Biology, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy
| | - Silvia Perego
- Laboratory of Experimental Biochemistry & Molecular Biology, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy
| | - Veronica Sansoni
- Laboratory of Experimental Biochemistry & Molecular Biology, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy
| | - Giuseppe Banfi
- Laboratory of Experimental Biochemistry & Molecular Biology, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
| | - Giovanni Lombardi
- Laboratory of Experimental Biochemistry & Molecular Biology, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy
- Department of Athletics, Strength and Conditioning, Poznań University of Physical Education, Poznań, Poland
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Abstract
Bone and skeletal muscle are integrated organs and their coupling has been considered mainly a mechanical one in which bone serves as attachment site to muscle while muscle applies load to bone and regulates bone metabolism. However, skeletal muscle can affect bone homeostasis also in a non-mechanical fashion, i.e., through its endocrine activity. Being recognized as an endocrine organ itself, skeletal muscle secretes a panel of cytokines and proteins named myokines, synthesized and secreted by myocytes in response to muscle contraction. Myokines exert an autocrine function in regulating muscle metabolism as well as a paracrine/endocrine regulatory function on distant organs and tissues, such as bone, adipose tissue, brain and liver. Physical activity is the primary physiological stimulus for bone anabolism (and/or catabolism) through the production and secretion of myokines, such as IL-6, irisin, IGF-1, FGF2, beside the direct effect of loading. Importantly, exercise-induced myokine can exert an anti-inflammatory action that is able to counteract not only acute inflammation due to an infection, but also a condition of chronic low-grade inflammation raised as consequence of physical inactivity, aging or metabolic disorders (i.e., obesity, type 2 diabetes mellitus). In this review article, we will discuss the effects that some of the most studied exercise-induced myokines exert on bone formation and bone resorption, as well as a brief overview of the anti-inflammatory effects of myokines during the onset pathological conditions characterized by the development a systemic low-grade inflammation, such as sarcopenia, obesity and aging.
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Affiliation(s)
- Marta Gomarasca
- IRCCS Istituto Ortopedico Galeazzi, Laboratory of Experimental Biochemistry & Molecular Biology, Milan, Italy
| | - Giuseppe Banfi
- IRCCS Istituto Ortopedico Galeazzi, Laboratory of Experimental Biochemistry & Molecular Biology, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy
| | - Giovanni Lombardi
- IRCCS Istituto Ortopedico Galeazzi, Laboratory of Experimental Biochemistry & Molecular Biology, Milan, Italy; Gdańsk University of Physical Education & Sport, Gdańsk, Pomorskie, Poland.
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Banitalebi E, Kazemi A, Faramarzi M, Nasiri S, Haghighi MM. Effects of sprint interval or combined aerobic and resistance training on myokines in overweight women with type 2 diabetes: A randomized controlled trial. Life Sci 2018; 217:101-109. [PMID: 30508516 DOI: 10.1016/j.lfs.2018.11.062] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Revised: 11/23/2018] [Accepted: 11/29/2018] [Indexed: 12/22/2022]
Abstract
Our primary aim was to assess the effects of two different training modalities: sprint interval training (SIT) or combined aerobic and resistance training (A + R) on circulating myokines related to metabolic profile and adiposity in type 2 diabetes (T2D). Fifty-two overweight women with T2D [55 ± 6 yrs., BMI 28.9 ± 4.1 kg/m2, HbA1c 9.4 ± 0.82% (79 mmol/mol)] were randomized to SIT (n = 17), A + R training (n = 17) or control (n = 18) for 10 weeks. Myokines, metabolic outcomes, body composition and cardiorespiratory fitness were assessed at baseline and 48 hours after the last training session/control period. Relationships between myokines and other variables were investigated via linear regression models. Completion rate was 81%. There was no effect of either exercise modality on any myokine. Interlukin-15 decreased over time irrespective of group assignment (p = 0.02). Aerobic capacity (p = 0.01), fasting glucose (p = 0.03) and HbA1c (p = 0.006) improved significantly and similarly in both exercise groups compared to controls. Insulin (p = 0.02), weight (p = 0.020, body max index (BMI) (p = 0.01) decreased significantly over time irrespective of group. Changes in myokines were unrelated to changes in body composition or metabolic profile. Neither SIT or A + R training altered myokines measured 48 h after exercise in T2D, despite improving aerobic capacity and glucose homeostasis relative to controls. Future studies are needed to elucidate the time course and clinical relevance of putative myokine responses to exercise in this and other cohorts.
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Affiliation(s)
| | - AbdolReza Kazemi
- Department of Sport Sciences, Valiaaser University, Rafsanjan, Kerman, Iran
| | | | - Samira Nasiri
- Department of Sport Sciences, Shahrekord University, Shahrekord, Iran
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Vitale JA, Lombardi G, Weydahl A, Banfi G. Biological rhythms, chronodisruption and chrono-enhancement: The role of physical activity as synchronizer in correcting steroids circadian rhythm in metabolic dysfunctions and cancer. Chronobiol Int 2018; 35:1185-1197. [DOI: 10.1080/07420528.2018.1475395] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Affiliation(s)
- Jacopo Antonino Vitale
- Laboratory of Biological Structure Biomechanics, IRCCS Istituto Ortopedico Galeazzi, Milano, Italia
| | - Giovanni Lombardi
- Laboratory of Experimental Biochemistry & Molecular Biology, IRCCS Istituto Ortopedico Galeazzi, Milano, Italia
| | - Andi Weydahl
- UiT-The Arctic University of Norway, Alta, Norway
| | - Giuseppe Banfi
- Laboratory of Experimental Biochemistry & Molecular Biology, IRCCS Istituto Ortopedico Galeazzi, Milano, Italia
- Vita-Salute San Raffaele University, Milano, Italia
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Son JS, Chae SA, Testroet ED, Du M, Jun HP. Exercise-induced myokines: a brief review of controversial issues of this decade. Expert Rev Endocrinol Metab 2018; 13:51-58. [PMID: 30063442 DOI: 10.1080/17446651.2018.1416290] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
INTRODUCTION Myokines, known to mediate metabolism, inflammation, and other pathophysiological conditions, have been widely investigated, including myokines induced by exercise. However, among published literature, there is substantial inconsistency in the quantification of exercise-induced myokines. Here, we summarized and compared published data regarding the effects of exercise on commonly studied myokines including apelin, Brain-derived neurotrophic factor (BDNF), Interleukin-15 (IL-15), irisin, and Secreted protein acidic and rich in cysteine (SPARC) during the last decade and discussed possible reasons for discrepancy in these reports. AREAS COVERED A search on PubMed for original articles published in this decade was conducted, focusing on the impacts of exercises on myokines and metabolic and age-related disorders. Beneficial relationship between skeletal muscle plasticity and myokines due to exercise is also discussed. EXPERT COMMENTARY Based on these analyses, exercise induces the secretion of a number of myokines, which has positive effects on metabolic diseases or age-related muscle atrophy (sarcopenia). However, among published reports, there is wide discrepancy in the quantification of myokines induced by exercise, which could be due to timing of sample collection, pre-analytic sample processing, analytical method, and calculation and other factors. Thus, these factors need to be considered in future studies on exercise induced myokines.
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Affiliation(s)
- Jun Seok Son
- a Nutrigenomics and Growth Biology Laboratory, Department of Animal Sciences , Washington State University , Pullman , WA , USA
| | - Song Ah Chae
- b Department of Movement Sciences , University of Idaho , Moscow , ID , USA
| | - Eric D Testroet
- a Nutrigenomics and Growth Biology Laboratory, Department of Animal Sciences , Washington State University , Pullman , WA , USA
| | - Min Du
- a Nutrigenomics and Growth Biology Laboratory, Department of Animal Sciences , Washington State University , Pullman , WA , USA
| | - Hyung-Pil Jun
- b Department of Movement Sciences , University of Idaho , Moscow , ID , USA
- c Yonsei Institute of Sport Science and Exercise Medicine , Seoul , South Korea
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Lombardi G, Sansoni V, Banfi G. Measuring myokines with cardiovascular functions: pre-analytical variables affecting the analytical output. ANNALS OF TRANSLATIONAL MEDICINE 2017; 5:299. [PMID: 28856139 PMCID: PMC5555982 DOI: 10.21037/atm.2017.07.11] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/24/2017] [Accepted: 06/28/2017] [Indexed: 12/30/2022]
Abstract
In the last few years, a growing number of molecules have been associated to an endocrine function of the skeletal muscle. Circulating myokine levels, in turn, have been associated with several pathophysiological conditions including the cardiovascular ones. However, data from different studies are often not completely comparable or even discordant. This would be due, at least in part, to the whole set of situations related to the preparation of the patient prior to blood sampling, blood sampling procedure, processing and/or store. This entire process constitutes the pre-analytical phase. The importance of the pre-analytical phase is often not considered. However, in routine diagnostics, the 70% of the errors are in this phase. Moreover, errors during the pre-analytical phase are carried over in the analytical phase and affects the final output. In research, for example, when samples are collected over a long time and by different laboratories, a standardized procedure for sample collecting and the correct procedure for sample storage are acknowledged. In this review, we discuss the pre-analytical variables potentially affecting the measurement of myokines with cardiovascular functions.
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Affiliation(s)
- Giovanni Lombardi
- Laboratory of Experimental Biochemistry & Molecular Biology, IRCCS Galeazzi Orthopaedic Institute, Milan, Italy
| | - Veronica Sansoni
- Laboratory of Experimental Biochemistry & Molecular Biology, IRCCS Galeazzi Orthopaedic Institute, Milan, Italy
| | - Giuseppe Banfi
- Laboratory of Experimental Biochemistry & Molecular Biology, IRCCS Galeazzi Orthopaedic Institute, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
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