Handgrip strength is a vital marker of muscle function and predictor of health outcomes in older adults. This study investigated the relationship between the muscle-to-fat ratio and 3-year decrease in handgrip strength in community-dwelling adults aged ≥50 years.

Data were obtained from the Longitudinal Aging Study of Taipei (LAST), a cohort study of adults aged 50 years and older. Measurements from two waves, 3 years apart, were analyzed. Demographics, laboratory data, and handgrip strength data were collected. Appendicular skeletal muscle mass was assessed using bioimpedance analysis, and the relative appendicular skeletal muscle mass index was calculated by dividing appendicular muscle mass by height squared. The muscle-to-fat ratio was derived by dividing appendicular muscle mass by total body fat. Handgrip strength decrease was divided into quartiles; slow decliners experienced the smallest decrease, whereas rapid decliners had the greatest decrease. Associations between the muscle-to-fat ratio and other risk factors were analyzed.

Over 3 years, the Charlson Comorbidity Index, medication use, waist-to-hip ratio, and fat percentage increased, whereas skeletal muscle mass, the muscle-to-fat ratio, and handgrip strength decreased. Rapid decliners were less likely to be male (21.6% vs 33.3%, p = 0.008) or alcohol drinkers (53.8% vs 66.2%, p = 0.01) and had lower skeletal muscle mass (6.3 ± 0.9 vs 6.6 ± 1.0, p = 0.006) and muscle-to-fat ratios (1.0 ± 0.4 vs 1.1 ± 0.5, p = 0.004) but greater fat percentages (30.4 ± 6.6 vs 29.0 ± 7.6, p = 0.045). A greater muscle-to-fat ratio (odds ratio [OR] = 3.751, p = 0.047), greater physical activity (OR = 1.694, p = 0.04), and lower glycated hemoglobin (HbA1c; OR = 0.61, p = 0.008) reduced the risk of rapid decline.

The muscle-to-fat ratio, together with physical activity and glycemic control, predicts a decrease in handgrip strength, highlighting its potential as a biomarker of intrinsic capacity and muscle-fat interplay. Further research is needed to explore the underlying biological mechanisms involved.

Diabetes patients' quality of life can be severely impacted by diabetic muscle atrophy.

This study aimed to explore the impact of high-intensity exercise (HIE) alongside insulin treatment on muscle atrophy in a rat model of type 1 diabetes mellitus (T1DM).

Fifty rats were allocated into five groups; Group 1, control sedentary (CS), T1DM was elicited in the rest of the groups by giving them Streptozotocin (STZ) (60 mg/kg), where group 2 (DS) remained sedentary, while groups 3,4,5 were treated with insulin after induction of diabetes. Group 4 (DI+MIE) and 5 (DI+ HIE) underwent moderate and high-intensity exercise, respectively.

HIE for 14 days combined with insulin treatment significantly restored muscle strength and mass with a significant modification in the mitophagy-related proteins and fibroblast growth factor 21 (FGF 21) compared to other treated groups.

This study concluded that there is a therapeutic role for HIE with insulin against T1DM-induced muscle atrophy.

Rotator cuff injury (RCI) is a common musculoskeletal problem that can have a significant impact on the quality of life and functional abilities of those affected. Novel therapies, including proteomics-based, stem cells, platelet-rich plasma, and exosomes, are being developed to promote rotator-cuff healing. The receptor for advanced glycation end-products (RAGE) is a multifunctional receptor that is expressed on several cell types and is implicated in several physiologic and pathological processes, such as tissue repair, inflammation, and degeneration. Because of its capacity to bind with a variety of ligands and initiate signaling pathways that lead to inflammatory responses in RCI, RAGE plays a crucial role in inflammation. In this critical review article, we discussed the role of RAGE-mediated persistent inflammation in RCI followed by novel factors including PKCs, TIRAP, DIAPH1, and factors related to muscle injury with their therapeutic potential in RCI. These factors involve various aspects of muscle injury and signaling and the possibility of targeting these factors to improve the clinical outcomes in RCI still needs further investigation.

Skeletal muscle atrophy is a clinical concern in diabetic nephropathy, and without effective therapeutic approaches. Massive evidence has demonstrated that dapagliflozin, a sodium-glucose co-transporter 2 inhibitor can relieve diabetic nephropathy by inhibiting glucose re-absorption or podocyte pyroptosis. Nevertheless, whether dapagliflozin could treat skeletal muscle atrophy or the potential protection mechanism in diabetic nephropathy mice is unclear.

The variety of approaches were used to assess the particular histology-associated characteristics, mRNA, and protein expression. These included examing the morphology of renal and skeletal muscle tissues through H&E staining, detecting mRNA and protein expression through real-time PCR and Western blot analysis, and monitoring fasting blood glucose levels by using Blood Glucose Monitor Test Kits.

Dapagliflozin mitigated renal tissue injury with podocyte protein-nephrin and skeletal muscle atrophy effectively with mitochondrial-related proteins. Meanwhile, our research revealed that Casp3 was the target gene and dapagliflozin could decrease the expressions. Subsequently, we verified that dapagliflozin can effectively decrease canonical pyroptosis pathway proteins, which include Gasdermin D, NLRP3, Casp1, and ASC. Meanwhile, Palmitic acid (PA) induced Gasdermin E-N fragment (non-canonical pyroptosis protein) in C2C12 cells, and then released the inflammatory molecules such as IL-1β, IL-18, and NF-kappaB, which were suppressed by dapagliflozin treatment. Aside from that, dapagliflozin demonstrated a good binding affinity to the Casp3 and Gasdermin D protein, whereas it had a less binding affinity with NLRP3, Casp1, ASC, and Gasdermin E. At last, the Gasdermin D inhibitor can reverse the therapeutic effect of dapagliflozin.

Dapagliflozin alleviates skeletal muscle atrophy in diabetic nephropathy mice, which is through the Gasdermin D-mediated canonical pyroptosis pathway.

Muscle disuse and offloading in microgravity are likely the primary factors mediating spaceflight-induced muscle atrophy, for which there is currently no effective treatment other than exercise. Extracellular vesicles derived from bone marrow mesenchymal stem cells (BMSC-EVs) possess anti-inflammatory and antioxidant properties, offering a potential strategy for combating weightless muscular atrophy.

In this study, human BMSCs-EVs (hBMSC-EVs) were isolated using super-centrifugation and characterized. C2C12 myotube nutrition-deprivation and mice tail suspension models were established. Subsequently, the diameter of C2C12 myotubes, Soleus mass, cross-sectional area (CSA) of muscle fibers, and grip strength in mice were assessed to investigate the impact of hBMSC-EVs on muscle atrophy. Immunostaining, transmission electron microscopy observation, and western blot analysis were employed to assess the impact of hBMSC-EVs on muscle fiber types, ROS levels, inflammation, ubiquitin-proteasome system activity, and autophagy lysosome pathway activation in skeletal muscle atrophy.

The active hBMSC-EVs can be internalized by C2C12 myotubes and skeletal muscle. hBMSC-EVs can effectively reduce C2C12 myotube atrophy caused by nutritional deprivation, with a concentration of 10 × 108 particles/mL showing the best effect (P < 0.001). Additionally, hBMSC-EVs can down-regulate the protein levels associated with UPS and oxidative stress. Moreover, intravenous administration of hBMSC-EVs at a concentration of 1 × 1010 particles/mL can effectively reverse the reduction in soleus mass (P < 0.001), CSA (P < 0.01), and grip strength (P < 0.001) in mice caused by weightlessness. They demonstrate the ability to inhibit protein degradation mediated by UPS and autophagy lysosome pathway, along with the suppression of oxidative stress and inflammatory responses. Furthermore, hBMSC-EVs impede the transition of slow muscle fibers to fast muscle fibers via upregulation of Sirt1 and PGC-1α protein levels.

Our findings indicate that hBMSC-EVs are capable of inhibiting excessive activation of the UPS and autophagy lysosome pathway, suppressing oxidative stress and inflammatory response, reversing muscle fiber type transformation, effectively delaying hindlimb unloading-induced muscle atrophy and enhancing muscle function. Our study has further advanced the understanding of the molecular mechanism underlying muscle atrophy in weightlessness and has demonstrated the protective effect of hBMSC-EVs on muscle atrophy.

One of the most critical factors impacting healthspan in the elderly is the loss of muscle mass and function, clinically referred to as sarcopenia. Muscle atrophy and weakness lead to loss of mobility, increased risk of injury, metabolic changes and loss of independence. Thus, defining the underlying mechanisms of sarcopenia is imperative to enable the development of effective interventions to preserve muscle function and quality in the elderly and improve healthspan. Over the past few decades, understanding the roles of mitochondrial dysfunction and oxidative stress has been a major focus of studies seeking to reveal critical molecular pathways impacted during aging. In this review, we will highlight how oxidative stress might contribute to sarcopenia by discussing the impact of oxidative stress on the loss of innervation and alteration in the neuromuscular junction (NMJ), on muscle mitochondrial function and atrophy pathways, and finally on muscle contractile function.

With the development of medicine and chemistry, an increasing number of plant-derived medicines have been shown to exert beneficial therapeutic on the treatment of various physical and psychological diseases. In particular, by using physical chemistry methods, we are able to examine the chemical components of plants and the effects of these substances on the human body. Muscle atrophy (MA) is characterized by decreased muscle mass and function, is caused by multiple factors and severely affects the quality of life of patients. The multifactorial and complex pathogenesis of MA hinders drug research and disease treatment. However, phytotherapy has achieved significant results in the treatment of MA. We searched PubMed and the Web of Science for articles related to plant-derived substances and muscle atrophy. After applying exclusion and inclusion criteria, 166 and 79 articles met the inclusion criteria, respectively. A total of 173 articles were included in the study after excluding duplicates. The important role of phytoactives such as curcumin, resveratrol, and ginsenosides in the treatment of MA (e.g., maintaining a positive nitrogen balance in muscles and exerting anti-inflammatory and antioxidant effects) has been extensively studied. Unfortunately, MA dose not have to a single cause, and each cause has its own unique mechanism of injury. This review focuses on the therapeutic mechanisms of active plant components in MA and provides insights into the personalized treatment of MA.

This study aimed to evaluate the effects of 4-hexylresorcinol (4HR), a synthetic compound with antioxidant and stress-modulating properties, on diabetic sarcopenia in the masseter muscle.

A controlled, parallel-arm study was conducted using 38 Sprague-Dawley rats divided into diabetic and non-diabetic groups. Diabetes was induced with streptozotocin (STZ), and the groups were further subdivided to receive weekly subcutaneous injections of either 4HR or saline. Muscle volume was assessed using micro-computed tomography (μCT), and glycogen storage and protein expression were analyzed using periodic acid-Schiff (PAS) staining and immunohistochemistry.

μCT analysis revealed that diabetic rats exhibited significantly reduced masseter muscle volume compared to non-diabetic rats. However, 4HR treatment partially mitigated muscle volume loss in diabetic animals. Histological analysis showed higher PAS staining intensity in the diabetic group treated with 4HR compared to the untreated diabetic group, suggesting improved glycogen storage. Immunohistochemistry demonstrated that 4HR treatment significantly increased Glut4 and phosphorylated AMPKα (p-AMPKα) expression in diabetic muscle, indicating enhanced glucose uptake and metabolic activity.

4HR effectively alleviates diabetes-induced sarcopenia by preserving muscle volume, enhancing glycogen storage, and upregulating Glut4 and p-AMPKα expression. These findings suggest that 4HR holds potential as a therapeutic agent for combating muscle wasting in diabetes.

Skeletal muscle (SM) is essential for movement, stability, and overall body function, and it readily adapts to changes in energy demand. Myogenesis is energy-intensive and involves complex molecular and cellular events. We recently demonstrated that the absence of lysosomal acid lipase (LAL) in vivo significantly impacts the SM phenotype, primarily by disrupting energy homeostasis and reducing ATP production. As systemic LAL deficiency affects multiple organs, we hypothesized that the altered SM phenotype resulted from systemic rather than SM-specific loss of LAL activity. To distinguish between systemic and cell-intrinsic effects, we used primary myoblasts isolated from Lal-deficient (-/-) mice as well as C2C12 cells treated with the pharmacological inhibitor of LAL, Lalistat-2. We found a significant accumulation of cholesteryl esters in both models studied, highlighting the central role of LAL in lipid catabolism in the SM. However, lipid accumulation was absent under lipoprotein-deficient culture conditions. Neither genetic loss nor pharmacological inhibition of LAL affected myofiber formation or mitochondrial function in vitro, in contrast to what we observed in SM isolated from Lal-/- mice. Tracing [13C6]-labeled glucose in both cell culture models revealed only minor changes in tricarboxylic acid cycle metabolites. These results suggest that although LAL plays an essential role in lipid metabolism, its impact on the processes involved in muscle differentiation and cellular energy production is minor. We conclude that the cell-intrinsic effects of Lal-/- SM are unlikely to drive the SM phenotype observed in vivo.

Patients with diabetes mellitus (DM) have an increased risk of tooth decay caused by alterations in their tooth development and their oral environment, as well as a tendency to present with pulp infection due to compromised immune response. The present study analyzed the characteristic alterations in tooth development under DM conditions using incisors from db/db type 2 diabetic mouse model (T2DM mice). In micro-CT analyses, T2DM mice showed delayed dentin and enamel formation. Through transcriptomic analyses, pre-ameloblast- and pre-odontoblast-specific genes were found to be significantly decreased in the incisors of T2DM mice, whereas major ameloblast- and mature odontoblast-specific genes were not changed. Stem cell markers were decreased in T2DM mice compared to those from the control mice, suggesting that the stemness of dental pulp cells (DPCs) is attenuated in T2DM mice. In vitro analyses demonstrated that DPCs from T2DM mice have lower colony-forming units (CFU), slower propagation, and diminished differentiation characteristics compared to the control. These data suggest that T2DM conditions could impair the differentiation property of multiple progenitor/stem cells in the tooth, resulting in delayed tooth development in T2DM mice.

Sarcopenia, characterized by progressive and generalized loss of skeletal muscle (SkM) mass, strength, and physical performance, is a prevalent complication in type 2 diabetes (T2D). Nitric oxide (NO), a multifunctional gasotransmitter involved in whole-body glucose and insulin homeostasis, plays key roles in normal SkM physiology and function. Here, we highlight the role of NO in SkM mass maintenance and its potential contribution to the development of T2D-related sarcopenia. Physiologic NO level, primarily produced by sarcolemmal neuronal nitric oxide synthase (nNOSμ isoform), is involved in protein synthesis in muscle fibers and maintenance of SkM mass. The observed effect of nNOSμ on SkM mass is muscle-type specific and sex-dependent. Impaired NO homeostasis [due to a diminished nNOSμ-NO availability and excessive NO production through inducible NOS (iNOS) in response to atrophic stimuli, e.g., inflammatory cytokines] in SkM occurred during the development and progression of T2D, may cause sarcopenia. Theoretically, restoration of NO through nNOS overexpression, supplying NOS substrates (e.g., L-arginine and L-citrulline), phosphodiesterase (PDE) inhibition, and supplementation with NO donors (e.g., inorganic nitrate) may be potential therapeutic approaches to preserve SkM mass and prevents sarcopenia in T2D.

Sarcopenia is a loss of muscle strength, muscle mass, and function that can increase a patient's risk of injury, illness, and can even severely impair quality of life and increase a patient's risk of death. A growing body of research suggests that sarcopenia and urinary tract disorders are closely related. In this review, we aimed to emphasize the definition of skeletal sarcopenia, summarize the methods used to diagnose skeletal sarcopenia, discuss the advances in the study of sarcopenia in benign diseases of the urinary system, discuss the advances in the study of sarcopenia in malignant diseases of the urinary system. Sarcopenia and urologic diseases interact with each other; urologic diseases cause sarcopenia, and sarcopenia aggravates the condition of the original disease, thus falling into a vicious circle. This review provides a comprehensive understanding of sarcopenia in urologic diseases, which is very important for the management and prognosis of urologic diseases.

The exploration of novel therapeutic avenues for skeletal muscle atrophy is imperative due to its significant health impact. Recent studies have spotlighted growth differentiation factor 11 (GDF11), a TGFβ superfamily member, for its rejuvenating role in reversing age-related tissue dysfunction. This review synthesizes current findings on GDF11, elucidating its distinct biological functions and the ongoing debates regarding its efficacy in muscle homeostasis. By addressing discrepancies in current research outcomes and its ambiguous role due to its homological identity to myostatin, a negative regulator of muscle mass, this review aims to clarify the role of GDF11 in muscle homeostasis and its potential as a therapeutic target for muscle atrophy. Through a thorough examination of GDF11's mechanisms and effects, this review provides insights that could pave the way for innovative treatments for muscle atrophy, emphasizing the need and strategies to boost endogenous GDF11 levels for therapeutic potential.

Obesity and type 2 diabetes mellitus (T2DM) are increasingly common in the United States and worldwide. Because both conditions are associated with serious health consequences, weight reduction is recommended by professional medical and nutrition societies to improve outcomes. Due to the striking efficacy of glucagon-like peptide receptor agonists (GLP-1RAs) and dual mechanism glucose-dependent insulinotropic polypeptide/glucagon-like peptide receptor agonists (GIP/GLP-1RAs) for weight reduction and glycemic control, there is increased utilization for patients with obesity and/or T2DM. Yet, the impact of these medications on dietary intake is less understood.

This narrative literature review summarizes clinical studies quantifying and characterizing dietary intake in people with obesity and/or T2DM using GLP-1 or GIP/GLP-1 RAs.

Though data from these studies reveal that total caloric intake was reduced by 16-39 %, few studies evaluated the actual composition of the diet.

Further research is needed to understand the unique nutritional needs of adults on GLP-1 or dual GIP/GLP-1RAs and to support the development of nutritional guidelines for these individuals.

Diabetic muscular atrophy is becoming a fast-growing problem worldwide, including sarcopenia, which is associated with substantial mortality and morbidity risk. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been marketed and suggested to exert protective effects on not only glycemic control but also diabetic complications in diabetic patients. In this study, we investigated the therapeutic use of GLP-1RAs exendin-4, compared to antidiabetic drug metformin, for the intervention of muscular dysfunction during diabetic conditions using a streptozotocin (STZ)-induced diabetic mouse model. The results showed that both exendin-4 and metformin could effectively alleviate hyperglycemia in diabetic mice, and also counteract diabetes-induced muscle weight loss, weaker grip, and changes in muscle fiber cross-sectional area distribution. Unexpectedly, exendin-4, but not metformin, enhanced the increased kidney weight and histological change in diabetic mice. Taken together, these findings suggest that both exendin-4 and metformin could effectively improve the diabetic hyperglycemia and muscular dysfunction; but exendin-4 may aggravate the nephropathy in STZ-induced diabetic mice.

Diabetes has become a serious public health crisis, presenting significant challenges to individuals worldwide. As the largest organ in the human body, skeletal muscle is a significant target of this chronic disease, yet muscle wasting as a complication of diabetes is still not fully understood and effective treatment methods have yet to be developed. Here, we discuss the targets involved in inducing muscle wasting under diabetic conditions, both validated targets and emerging targets. Diabetes-induced skeletal muscle wasting is known to involve changes in various signaling molecules and pathways, such as protein degradation pathways, protein synthesis pathways, mitochondrial function, and oxidative stress inflammation. Recent studies have shown that some of these present potential as promising therapeutic targets, including the neuregulin 1/epidermal growth factor receptor family, advanced glycation end-products, irisin, ferroptosis, growth differentiation factor 15 and more. This study's investigation and discussion of such pathways and their potential applications provides a theoretical basis for the development of clinical treatments for diabetes-induced muscle wasting and a foundation for continued focus on this disease.

Sarcopenia refers to an age-related decrease in muscle mass and strength. The gut-muscle axis has been proposed as a promising target to alleviate muscle atrophy. The effect of KL-Biome-a postbiotic preparation comprising heat-killed Lactiplantibacillus plantarum KM-2, its metabolites, and an excipient (soybean powder)-on muscle atrophy was evaluated using dexamethasone (DEX)-induced atrophic C2C12 myoblasts and C57BL/6J mice. KL-Biome significantly downregulated the expression of genes (Atrogin-1 and MuRF1) associated with skeletal muscle degradation but increased the anabolic phosphorylation of FoxO3a, Akt, and mTOR in C2C12 cells. Oral administration of KL-Biome (900 mg/kg) for 8 weeks significantly improved muscle mass, muscle function, and serum lactate dehydrogenase levels in DEX-treated mice. KL-Biome administration increased gut microbiome diversity and reversed DEX-mediated gut microbiota alterations. Furthermore, it significantly increased the relative abundances of the genera Subdologranulum, Alistipes, and Faecalibacterium prausnitzii, which are substantially involved in short-chain fatty acid production. These findings suggest that KL-Biome exerts beneficial effects on muscle atrophy by regulating gut microbiota.

Tryptophan (TRP) metabolites along the kynurenine (KYN) pathway (KP) have been found to influence muscle. Proinflammatory cytokines are known to stimulate the degradation of TRP down the KP. Given that both inflammation and KP metabolites have been connected with loss of muscle, we assessed the potential mediating role of KP metabolites on inflammation and muscle mass in older men. Five hundred and five men (85.0 ± 4.2 years) from the Osteoporotic Fractures in Men cohort study with measured D3-creatine dilution (D3Cr) muscle mass, KP metabolites, and inflammation markers (C-reactive protein [CRP], alpha-1-acid glycoprotein [AGP] and a subsample [n = 305] with interleukin [IL-6, IL-1β, IL-17A] and tumor necrosis factor-α [TNF-α]) were included in the analysis. KP metabolites and inflammatory markers were measured using liquid chromatography-tandem mass spectrometry and immunoassays, respectively. 23%-92% of the inverse relationship between inflammatory markers and D3Cr muscle mass was mediated by KP metabolites (indirect effect p < .05). 3-hydroxyanthranilic acid (3-HAA), quinolinic acid (QA), TRP, xanthurenic acid (XA), KYN/TRP, 3-hydroxykynurenine (3-HK)/3-HAA, QA/3-HAA, and nicotinamide (NAM)/QA mediated the AGP relationship. 3-HAA, QA, KYN/TRP, 3-HK/XA, HKr ratio, 3-HK/3-HAA, QA/3-HAA, and NAM/QA mediated the CRP. KYN/TRP, 3-HK/XA, and NAM/QA explained the relationship for IL-6 and 3-HK/XA and QA/3-HAA for TNF-α. No mediation effect was observed for the other cytokines (indirect effect p > .05). KP metabolites, particularly higher ratios of KYN/TRP, 3-HK/XA, 3-HK/3-HAA, QA/3-HAA, and a lower ratio of NAM/QA, mediated the relationship between inflammation and low muscle mass. Our preliminary cross-sectional data suggest that interventions to alter D3Cr muscle mass may focus on KP metabolites rather than inflammation per se.

It is not well-understood how type 1 diabetes (T1DM) affects skeletal muscle histological phenotype, particularly capillarisation. This study aimed to analyze skeletal muscle myosin heavy chain (MyHC) fibre type changes and 3D capillary network characteristics in experimental T1DM mice. Female C57BL/6J-OlaHsd mice were categorized into streptozotocin (STZ)-induced diabetic (n = 12) and age-matched non-diabetic controls (n =12). The muscle fibre phenotype of the soleus, gluteus maximus, and gastrocnemius muscles were characterized based on the expression of MyHC isoforms, while capillaries of the gluteus maximus were assessed with immunofluorescence staining, confocal laser microscopy and 3D image analysis. STZ-induced diabetic mice exhibited elevated glucose levels, reduced body weight, and prolonged thermal latency, verifying the T1DM phenotype. In both T1DM and non-diabetic mice, the gluteus maximus and gastrocnemius muscles predominantly expressed fast-twitch type 2b fibers, with no significant differences noted. However, the soleus muscle in non-diabetic mice had a greater proportion of type 2a fibers and comparable type 1 fiber densities (26.2 ± 14.6% vs 21.9 ± 13.5%) relative to diabetic mice. T1DM mice showed reduced fiber diameters (P = 0.026), and the 3D capillary network analysis indicated a higher capillary length per muscle volume in the gluteus maximus of diabetic mice compared to controls (P < 0.05). Overall, T1DM induced significant changes in the skeletal muscle, including shifts in MyHC fibre types, decreased fibre diameters, and increased relative capillarisation, possibly due to muscle fibre atrophy. Our findings emphasize the superior detail provided by the 3D analytical method for characterizing skeletal muscle capillary architecture, highlighting caution in interpreting 2D data for capillary changes in T1DM.

Skeletal muscle is essential in generating mechanical force and regulating energy metabolism and body temperature. Pathologies associated with muscle tissue often lead to impaired physical activity and imbalanced metabolism. Recently, ectodysplasin A2 receptor (EDA2R) signaling has been shown to promote muscle loss and glucose intolerance. Upregulated EDA2R expression in muscle tissue was associated with aging, denervation, cancer cachexia, and muscular dystrophies. Here, we describe the roles of EDA2R signaling in muscle pathophysiology, including muscle atrophy, insulin resistance, and aging-related sarcopenia. We also discuss the EDA2R pathway, which involves EDA-A2 as the ligand and nuclear factor (NF)κB-inducing kinase (NIK) as a downstream mediator, and the therapeutic potential of targeting these proteins in the treatment of muscle wasting and metabolic dysfunction.

Improving inflammation may serve as useful therapeutic interventions for the hindlimb unloading-induced disuse muscle atrophy. Celecoxib is a selective non-steroidal anti-inflammatory drug. We aimed to determine the role and mechanism of celecoxib in hindlimb unloading-induced disuse muscle atrophy. Celecoxib significantly attenuated the decrease in soleus muscle mass, hindlimb muscle function and the shift from slow- to fast-twitch muscle fibers caused by hindlimb unloading in rats. Importantly, celecoxib inhibited the increased expression of inflammatory factors, macrophage infiltration in damaged soleus muscle. Mechanistically, Celecoxib could significantly reduce oxidative stress and endoplasmic reticulum stress in soleus muscle of unloaded rats. Furthermore, celecoxib inhibited muscle proteolysis by reducing the levels of MAFbx, MuRF1, and autophagy related proteins maybe by inhibiting the activation of pro-inflammatory STAT3 pathway in vivo and in vitro. This study is the first to demonstrate that celecoxib can attenuate disuse muscle atrophy caused by hindlimb unloading via suppressing inflammation, oxidative stress and endoplasmic reticulum stress probably, improving target muscle function and reversing the shift of muscle fiber types by inhibiting STAT3 pathways-mediated inflammatory cascade. This study not only enriches the potential molecular regulatory mechanisms, but also provides new potential therapeutic targets for disuse muscle atrophy.

Skeletal muscle diseases, a broad category encompassing a myriad of afflictions such as acute muscle injury and muscular dystrophies, pose a significant health burden globally. These conditions often lead to muscle weakness, compromised mobility, and a diminished quality of life. In light of this, innovative and effective therapeutic strategies are fervently sought after. Exosomes, naturally extracellular vesicles with a diameter of 30-150 nm, pervade biological fluids. These microscopic entities harbor a host of biological molecules, including proteins, nucleic acids, and lipids, bearing a significant resemblance to their parent cells. The roles they play in the biological theater are manifold, influencing crucial physiological and pathological processes within the organism. In the context of skeletal muscle diseases, their potential extends beyond these roles, as they present a promising therapeutic target and a vehicle for targeted drug delivery. This potentially paves the way for significant clinical applications. This review aims to elucidate the mechanisms underpinning exosome action, their myriad biological functions, and the strides made in exosome research and application. A comprehensive exploration of the part played by exosomes in skeletal muscle repair and regeneration is undertaken. In addition, we delve into the use of exosomes in the therapeutic landscape of skeletal muscle diseases, providing a valuable reference for a deeper understanding of exosome applications in this realm. The concluding section encapsulates the prospective avenues for exosome research and the promising future they hold, underscoring the tremendous potential these diminutive vesicles possess in the field of skeletal muscle diseases. The Translational Potential of this Article. The comprehensive exploration of exosome's diverse biological functions and translational potential in the context of skeletal muscle diseases presented in this review underscores their promising future as a therapeutic target with significant clinical applications, thus paving the way for innovative and effective therapeutic strategies in this realm.

Diabetic muscle atrophy is an inflammation-related complication of type-2 diabetes mellitus (T2DM). Even though regular exercise prevents further deterioration of atrophic status, there is no effective mediator available for treatment and the underlying cellular mechanisms are less explored. In this study, we investigated the therapeutic potential of MCC950, a specific, small-molecule inhibitor of NLRP3, to treat pyroptosis and diabetic muscle atrophy in mice. Furthermore, we used MCC950 to intervene in the protective effects of aerobic exercise against muscle atrophy in diabetic mice. Blood and gastrocnemius muscle (GAS) samples were collected after 12 weeks of intervention and the atrophic state was assessed. We initially corroborated a diabetic muscle atrophy phenotype in db/db mice (D) by comparison with control m/m mice (W) by examining parameters such as fasting blood glucose (D vs. W: 24.47 ± 0.45 mmol L-1 vs. 4.26 ± 0.6 mmol L-1, p < 0.05), grip strength (D vs. W: 166.87 ± 15.19 g vs. 191.76 ± 14.13 g, p < 0.05), exercise time (D vs. W: 1082.38 ± 104.67 s vs. 1716 ± 168.55 s, p < 0.05) and exercise speed to exhaustion (D vs. W: 24.25 ± 2.12 m min-1 vs. 34.75 ± 2.66 m min-1, p < 0.05), GAS wet weight (D vs. W: 0.07 ± 0.01 g vs. 0.13 ± 0.01 g, p < 0.05), the ratio of GAS wet weight to body weight (D vs. W: 0.18 ± 0.01% vs. 0.54 ± 0.02%, p < 0.05), and muscle fiber cross-sectional area (FCSA) (D vs. W: 1875 ± 368.19 µm2 vs. 2747.83 ± 406.44 µm2, p < 0.05). We found that both MCC950 (10 mg kg-1) treatment and exercise improved the atrophic parameters that had deteriorated in the db/db mice, inhibited serum inflammatory markers and significantly attenuated pyroptosis in atrophic GAS. In addition, a combined MCC950 treatment with exercise (DEI) exhibited a further improvement in glucose uptake capacity and muscle performance. This combined treatment also improved the FCSA of GAS muscle indicated by Laminin immunofluorescence compared to the group with the inhibitor treatment alone (DI) (DEI vs. DI: 2597 ± 310.97 vs. 1974.67 ± 326.15 µm2, p < 0.05) or exercise only (DE) (DEI vs. DE: 2597 ± 310.97 vs. 2006.33 ± 263.468 µm2, p < 0.05). Intriguingly, the combination of MCC950 treatment and exercise significantly reduced NLRP3-mediated inflammatory factors such as cleaved-Caspase-1, GSDMD-N and prevented apoptosis and pyroptosis in atrophic GAS. These findings for the first time demonstrate that targeting NLRP3-mediated pyroptosis with MCC950 improves diabetic muscle homeostasis and muscle function. We also report that inhibiting pyroptosis by MCC950 can enhance the beneficial effects of aerobic exercise on diabetic muscle atrophy. Since T2DM and muscle atrophy are age-related diseases, the young mice used in the current study do not seem to fully reflect the characteristics of diabetic muscle atrophy. Considering the fragile nature of db/db mice and for the complete implementation of the exercise intervention, we used relatively young db/db mice and the atrophic state in the mice was thoroughly confirmed. Taken together, the current study comprehensively investigated the therapeutic effect of NLRP3-mediated pyroptosis inhibited by MCC950 on diabetic muscle mass, strength and exercise performance, as well as the synergistic effects of MCC950 and exercise intervention, therefore providing a novel strategy for the treatment of the disease.

Skeletal muscle is a highly specialized tissue composed of myofibres that performs crucial functions in movement and metabolism. In response to external stimuli and injuries, a range of stem/progenitor cells, with muscle stem cells or satellite cells (MuSCs) being the predominant cell type, are rapidly activated to repair and regenerate skeletal muscle within weeks. Under normal conditions, MuSCs remain in a quiescent state, but become proliferative and differentiate into new myofibres in response to injury. In addition to MuSCs, some interstitial progenitor cells (IPCs) such as fibro-adipogenic progenitors (FAPs), pericytes, interstitial stem cells expressing PW1 and negative for Pax7 (PICs), muscle side population cells (SPCs), CD133-positive cells and Twist2-positive cells have been identified as playing direct or indirect roles in regenerating muscle tissue. Here, we highlight the heterogeneity, molecular markers, and functional properties of these interstitial progenitor cells, and explore the role of muscle stem/progenitor cells in skeletal muscle homeostasis, aging, and muscle-related diseases. This review provides critical insights for future stem cell therapies aimed at treating muscle-related diseases.

Aim: Diabetic sarcopenia leads to disability and seriously affects the quality of life. Currently, there are no effective therapeutic strategies for diabetic sarcopenia. Our previous studies have shown that inflammation plays a critical role in skeletal muscle atrophy. Interestingly, the connection between chronic inflammation and diabetic complications has been revealed. However, the effects of non-steroidal anti-inflammatory drug celecoxib on diabetic sarcopenia remains unclear. Materials and Methods: The streptozotocin (streptozotocin)-induced diabetic sarcopenia model was established. Rotarod test and grip strength test were used to assess skeletal muscle function. Hematoxylin and eosin and immunofluorescence staining were performed to evaluate inflammatory infiltration and the morphology of motor endplates in skeletal muscles. Succinate dehydrogenase (SDH) staining was used to determine the number of succinate dehydrogenase-positive muscle fibers. Dihydroethidium staining was performed to assess the levels of reactive oxygen species (ROS). Western blot was used to measure the levels of proteins involved in inflammation, oxidative stress, endoplasmic reticulum stress, ubiquitination, and autophagic-lysosomal pathway. Transmission electron microscopy was used to evaluate mitophagy. Results: Celecoxib significantly ameliorated skeletal muscle atrophy, improving skeletal muscle function and preserving motor endplates in diabetic mice. Celecoxib also decreased infiltration of inflammatory cell, reduced the levels of IL-6 and TNF-α, and suppressed the activation of NF-κB, Stat3, and NLRP3 inflammasome pathways in diabetic skeletal muscles. Celecoxib decreased reactive oxygen species levels, downregulated the levels of Nox2 and Nox4, upregulated the levels of GPX1 and Nrf2, and further suppressed endoplasmic reticulum stress by inhibiting the activation of the Perk-EIF-2α-ATF4-Chop in diabetic skeletal muscles. Celecoxib also inhibited the levels of Foxo3a, Fbx32 and MuRF1 in the ubiquitin-proteasome system, as well as the levels of BNIP3, Beclin1, ATG7, and LC3Ⅱ in the autophagic-lysosomal system, and celecoxib protected mitochondria and promoted mitochondrial biogenesis by elevating the levels of SIRT1 and PGC1-α, increased the number of SDH-positive fibers in diabetic skeletal muscles. Conclusion: Celecoxib improved diabetic sarcopenia by inhibiting inflammation, oxidative stress, endoplasmic reticulum stress, and protecting mitochondria, and subsequently suppressing proteolytic systems. Our study provides evidences for the molecular mechanism and treatment of diabetic sarcopenia, and broaden the way for the new use of celecoxib in diabetic sarcopenia.

Today, type 2 diabetes mellitus (T2DM) and skeletal muscle atrophy (SMA) have become increasingly common occurrences. Whether the onset of T2DM increases the risk of SMA or vice versa has long been under investigation. Both conditions are associated with negative changes in skeletal muscle health, which can, in turn, lead to impaired physical function, a lowered quality of life, and an increased risk of mortality. Poor nutrition can exacerbate both T2DM and SMA. T2DM and SMA are linked by a vicious cycle of events that reinforce and worsen each other. Muscle insulin resistance appears to be the pathophysiological link between T2DM and SMA. To explore this association, our review (i) compiles evidence on the clinical association between T2DM and SMA, (ii) reviews mechanisms underlying biochemical changes in the muscles of people with or at risk of T2DM and SMA, and (iii) examines how nutritional therapy and increased physical activity as muscle-targeted treatments benefit this population. Based on the evidence, we conclude that effective treatment of patients with T2DM-SMA depends on the restoration and maintenance of muscle mass. We thus propose that regular intake of key functional nutrients, along with guidance for physical activity, can help maintain euglycemia and improve muscle status in all patients with T2DM and SMA.

Oxidative stress, regulated by SOD2 and mitochondrial dynamics, contributes to muscle atrophy in diabetes. Ginger root extract (GRE) reduces oxidative stress. However, its effect on oxidative stress, mitochondrial dynamics, and muscle atrophy is not known in the diabetic muscle. This study examined the effect of GRE on intramuscular oxidative stress, mitochondrial dynamics, and muscle size in diabetic rats.

Twenty-six male Sprague-Dawley rats were randomly divided into control diet (CON; n=10), high-fat diet with one dose of 35 mg/kg streptozotocin (HFD; n=9), and high-fat diet with one dose of 35 mg/kg streptozotocin and 0.75% w/w GRE (GRE; n=7) fed for seven weeks. Subsequently, the muscle was analyzed for cross-sectional area (CSA), H2O2 concentration, and DRP-1, MFN2, Parkin, PINK1, SOD2 mRNA. Additionally, the protein levels of SOD2, DRP-1, DRP-1ser616, LC3AB, MFN2, OPA1, Parkin, and PINK1 were analyzed. CSA, H2O2 concentration, and gene and protein expression levels were analyzed using a one-way ANOVA. Correlations among intramuscular H2O2, CSA, and SOD2 protein were assessed using Pearson's bivariate correlation test.

In the soleus, the GRE group had a greater CSA and lower intramuscular H2O2 concentration compared to the HFD group. Compared to the HFD group, the GRE group had higher SOD2 and DRP-1 mRNA levels and lower MFN2 and total OPA1 protein levels. H2O2 concentration was negatively correlated with CSA and positively correlated with SOD2.

GRE attenuated intramuscular H2O2, mitochondrial fusion, and muscle size loss. These findings suggest that GRE supplementation in diabetic rats reduces oxidative stress, which may contribute to muscle size preservation.

Emerging evidence suggests that the ubiquitin-mediated degradation of insulin-signalling-related proteins may be involved in the development of insulin resistance and its related disorders. Tripartite motif-containing (TRIM) proteins, a superfamily belonging to the E3 ubiquitin ligases, are capable of controlling protein levels and function by ubiquitination, which is essential for the modulation of insulin sensitivity. Recent research has indicated that some of these TRIMs act as key regulatory factors of metabolic disorders such as type 2 diabetes mellitus, obesity, nonalcoholic fatty liver disease, and atherosclerosis. This review provides a comprehensive overview of the latest evidence linking TRIMs to the regulation of insulin resistance and its related disorders, their roles in regulating multiple signalling pathways or cellular processes, such as insulin signalling pathways, peroxisome proliferator-activated receptor signalling pathways, glucose and lipid metabolism, the inflammatory response, and cell cycle control, as well as recent advances in the development of TRIM-targeted drugs.

No effective drugs for the treatment of sepsis-induced diaphragm dysfunction are currently available. Therefore, it is particularly important to clarify the molecular regulatory mechanism of this condition and subsequently implement effective treatment and prevention of sepsis-induced diaphragm dysfunction.

A mouse model of diaphragm dysfunction was established via injection of lipopolysaccharide (LPS). An RNA-sequencing (RNA-seq) technique was used to detect the differentially expressed genes (DEGs) in the diaphragms of mice. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed for functional analysis of DEGs. The protein-protein interaction network obtained from the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) website was imported into Cytoscape, the key molecular regulatory network was constructed with CytoNCA, the ClueGo plugin was further used to analyze the core regulatory pathways of key molecular, and finally, the iRegulon plugin was used to the identify key transcription factors.

The genes upregulated after LPS treatment were involved in biological processes and pathways related to immune response; the genes downregulated after LPS treatment were mainly correlated with the muscle contraction. The expressions of several inflammation-related genes were upregulated after LPS treatment, of which tumor necrosis factor (Tnf), interleukin (Il)-1β, and Il-6 assumed a core regulatory role in the network; meanwhile, the downregulated key genes included Col1a1, Uqcrfs1, Sdhb, and ATP5a1, among others. These key regulatory factors participated in the activation of Toll-like receptor (TLR) signaling pathway, nuclear factor (NF)-κB signaling pathway, and TNF signaling pathway as well as the inhibition of oxidative phosphorylation pathway, cardiac muscle contraction pathway, and citrate cycle pathway. Finally, RelA, IRF1, and STAT3, were identified as the key regulators in the early stage of diaphragmatic inflammatory response.

Sepsis-induced diaphragm dysfunction in mice is closely correlated with the activation of TLR signaling pathway, NF-κB signaling pathway, and TNF signaling pathway and the inhibition of oxidative phosphorylation pathway, cardiac muscle contraction pathway, and citrate cycle pathway. Our findings provide insight into the molecular mechanism of sepsis-induced diaphragm dysfunction in mice and provide a promising new strategy for targeted treatment of diaphragm dysfunction.

Muscle dysfunction is an early complication of diabetic peripheral neuropathy (DPN). As a convenient and low-cost tool, muscle ultrasound has been used to assess muscle quality and muscle mass. However, the relationship between different muscle ultrasound parameters and DPN is unclear.

This study was designed to investigate the relationship between ultrasound parameters of different muscles and DPN among patients with type 2 diabetes mellitus, including the rectus femoris (RF), tibialis anterior (TA), and medial head of gastrocnemius (MG).

The research enrolled 90 patients with type 2 diabetes mellitus (T2DM). All images were attained from both sides. Muscle measurements contained muscle thickness (MT), cross-sectional area (CSA), echo intensity (EI), and corrected EI. The binary logistic regression and multiple linear regression were used to investigate the association between muscle ultrasound parameters and DPN or vibration perception threshold (VPT).

EI, corrected EI, MT of MG, and EI of TA were associated with DPN separately after adjusting other clinical variates. Among these muscle parameters, the EI of MG had a better predictive value (OR: 1.114, 95% CI: 1.039, 1.196) of DPN. Combined with CSA of RF, peripheral artery disease (PAD), and sex, the corrected EI of MG was associated with the vibration perception threshold (VPT) (standard β = 0.242, p < 0.001), better than the EI of MG (standard β = 0.215, p = 0.002).

MG (MT, EI, and corrected EI) and TA (EI) were associated with DPN, respectively. CSA of RF and corrected EI or EI of MG combined with PAD and sex were associated with VPT significantly, which supported that muscle ultrasound might be a substantial quantitative tool for detecting the exercise benefits for DPN.

Complex pathophysiological changes accompany denervation-induced skeletal muscle atrophy, but no effective treatment strategies exist. Our previous study indicated that extracellular vesicles derived from skin-derived precursors-derived Schwann cells (SKP-SC-EVs) can effectively mitigate denervation-induced muscle atrophy. However, the specific molecular mechanism remains unclear.

In this study, we used bioinformatics methods to scrutinize the impact of SKP-SC-EVs on gene expression in denervation-induced skeletal muscle atrophy. We found that SKP-SC-EVs altered the expression of 358 genes in denervated skeletal muscles. The differentially expressed genes were predominantly participated in biological processes, including cell cycle, inflammation, immunity, and adhesion, and signaling pathways, such as FoxO and PI3K.Using the Molecular Complex Detection (MCODE) plugin, we identified the two clusters with the highest score: cluster 1 comprised 37 genes, and Cluster 2 consisted of 24 genes. Then, fifty hub genes were identified using CytoHubba. The intersection of Hub genes and genes obtained by MCODE showed that all 23 genes related to the cell cycle in Cluster 1 were hub genes, and 5 genes in Cluster 2 were hub genes and associated with inflammation.

Overall, the differentially expressed genes in denervated skeletal muscle following SKP-SC-EVs treatment are primarily linked to the cell cycle and inflammation. Consequently, promoting proliferation and inhibiting inflammation may be the critical process in which SKP-SC-EVs delay denervation-induced muscle atrophy. Our findings contribute to a better understanding of the molecular mechanism of SKP-SC-EVs delaying denervation-induced muscle atrophy, offering a promising new avenue for muscle atrophy treatment.

Denervation-induced muscle atrophy is complex disease involving multiple biological processes with unknown mechanisms. N6-methyladenosine (m6A) participates in skeletal muscle physiology by regulating multiple levels of RNA metabolism, but its impact on denervation-induced muscle atrophy is still unclear. Here, we aimed to explore the changes, functions, and molecular mechanisms of m6A RNA methylation during denervation-induced muscle atrophy.

During denervation-induced muscle atrophy, the m6A immunoprecipitation sequencing (MeRIP-seq) as well as enzyme-linked immunosorbent assay analysis were used to detect the changes of m6A modified RNAs and the involved biological processes. 3-deazidenosine (Daa) and R-2-hydroxyglutarate (R-2HG) were used to verify the roles of m6A RNA methylation. Through bioinformatics analysis combined with experimental verification, the regulatory roles and mechanisms of m6A RNA methylation had been explored.

There were many m6A modified RNAs with differences during denervation-induced muscle atrophy, and overall, they were mainly downregulated. After 72 h of denervation, the biological processes involved in the altered mRNA with m6A modification were mainly related to zinc ion binding, ubiquitin protein ligase activity, ATP binding and sequence-specific DNA binding and transcription coactivator activity. Daa reduced overall m6A levels in healthy skeletal muscles, which reduced skeletal muscle mass. On the contrary, the increase in m6A levels mediated by R-2HG alleviated denervation induced muscle atrophy. The m6A RNA methylation regulated skeletal muscle mass through ubiquitin-proteasome pathway.

This study indicated that decrease in m6A RNA methylation was a new symptom of denervation-induced muscle atrophy, and confirmed that targeting m6A alleviated denervation-induced muscle atrophy.

Diabetes accelerates muscle atrophy, leading to the deterioration of skeletal muscles. This study aimed to assess the potential of the β2-adrenoceptor agonist, salbutamol (SLB), to alleviate muscle atrophy in streptozotocin (STZ)-induced diabetic rats. Male Sprague Dawley rats were randomized into four groups (n=6): control, SLB, STZ (55 mg/kg, single i.p.), and STZ + SLB (6 mg/kg, orally for 4 weeks). After the final SLB dose, animals underwent tests to evaluate muscle strength and coordination, including forelimb grip strength, wire-hanging, actophotometer, rotarod, and footprint assessments. Rats were then sacrificed, and serum and gastrocnemius (GN) muscles were collected for further analysis. Serum evaluations included proinflammatory markers (tumor necrosis factor α, interleukin-1β, interleukin-6), muscle markers (creatine kinase, myostatin), testosterone, and lipidemic markers. Muscle oxidative stress (malonaldehyde, protein carbonyl), antioxidants (glutathione, catalase, superoxide dismutase), and histology were also performed. Additionally, 1H nuclear magnetic resonance serum profiling was conducted. SLB notably enhanced muscle grip strength, coordination, and antioxidant levels, while reduced proinflammatory markers and oxidative stress in STZ-induced diabetic rats. Reduced serum muscle biomarkers, increased testosterone, restored lipidemic levels, and improved muscle cellular architecture indicated SLB's positive effect on muscle condition in diabetic rats. Metabolomics profiling revealed that the STZ group significantly increased the phenylalanine-to-tyrosine ratio (PTR), lactate-to-pyruvate ratio (LPR), acetate, succinate, isobutyrate, and histidine. SLB administration restored these perturbed serum metabolites in the STZ-induced diabetic group. In conclusion, salbutamol significantly protected against skeletal muscle wasting in STZ-induced diabetic rats.

Sarcopenia remains one of the major pathological features of type 2 diabetes (T2D), especially in older individuals. This condition describes gradual loss of muscle mass, strength, and function that reduces the overall vitality and fitness, leading to increased hospitalizations and even fatalities to those affected. Preclinical evidence indicates that dysregulated mitochondrial dynamics, together with impaired activity of the NADPH oxidase system, are the major sources of oxidative stress that drive skeletal muscle damage in T2D. While patients with T2D also display relatively higher levels of circulating inflammatory markers in the serum, including high sensitivity-C-reactive protein, interleukin-6, and tumor necrosis factor-α that are independently linked with the deterioration of muscle function and sarcopenia in T2D. In fact, beyond reporting on the pathological consequences of both oxidative stress and inflammation, the current review highlights the importance of strengthening intracellular antioxidant systems to preserve muscle mass, strength, and function in individuals with T2D.

People with intellectual disabilities (ID) have a lower life expectancy than their peers without ID. A contributing factor to the lower life expectancy and early mortality could be sarcopenia: low muscle mass and low muscle function. In the general population, sarcopenia strongly predicts early mortality, but this association is unknown in people with ID. Therefore, this study aims to explore the association between sarcopenia and 5-year mortality in older adults with ID.

In the Healthy Ageing and Intellectual Disabilities (HA-ID) study, the prevalence of sarcopenia was measured at baseline among 884 older adults (≥50 years) with ID. All-cause mortality was measured over a 5-year follow-up period. Univariable and multivariable Cox proportional hazard models were applied to determine the association between sarcopenia (no sarcopenia, pre-sarcopenia, sarcopenia, severe sarcopenia) and early mortality, adjusted for age, sex, level of ID, presence of Down syndrome, and co-morbidity (chronic obstructive pulmonary disease, diabetes type 2 and metabolic syndrome).

The unadjusted hazard ratio (HR) for sarcopenia was 2.28 [95% confidence interval (CI) 1.48-3.42], P < 0.001), and 2.40 (95% CI 1.40-4.10, P = 0.001) for severe sarcopenia. When adjusted for age, sex, level of ID, and Down syndrome, sarcopenia (HR = 1.72, 95% CI 1.08-2.75, P = 0.022) and severe sarcopenia (HR = 1.86, 95% CI 1.07-3.23, P = 0.028) were significantly associated with early mortality. When additionally adjusted for co-morbidity, the adjusted HR decreased to 1.62 (95% CI 1.02-2.59, P = 0.043) and 1.81 (95% CI 1.04-3.15, P = 0.035) for sarcopenia and severe sarcopenia, respectively.

Sarcopenia is an independent risk factor for early mortality in older adults with ID over a 5-year follow-up period. Our results stress the need to delay the incidence and development of sarcopenia in older adults with ID.

Muscle atrophy is characterized by the loss of muscle function. Many efforts are being made to prevent muscle atrophy, and exercise is an important alternative. Methylglyoxal is a well-known causative agent of metabolic diseases and diabetic complications. This study aimed to evaluate whether methylglyoxal induces muscle atrophy and to evaluate the ameliorative effect of moderate-intensity aerobic exercise in a methylglyoxal-induced muscle atrophy animal model. Each mouse was randomly divided into three groups: control, methylglyoxal-treated, and methylglyoxal-treated within aerobic exercise. In the exercise group, each mouse was trained on a treadmill for 2 weeks. On the last day, all groups were evaluated for several atrophic behaviors and skeletal muscles, including the soleus, plantaris, gastrocnemius, and extensor digitorum longus were analyzed. In the exercise group, muscle mass was restored, causing in attenuation of muscle atrophy. The gastrocnemius and extensor digitorum longus muscles showed improved fiber cross-sectional area and reduced myofibrils. Further, they produced regulated atrophy-related proteins (i.e., muscle atrophy F-box, muscle RING-finger protein-1, and myosin heavy chain), indicating that aerobic exercise stimulated their muscle sensitivity to reverse skeletal muscle atrophy. In conclusion, shortness of the gastrocnemius caused by methylglyoxal may induce the dynamic imbalance of skeletal muscle atrophy, thus methylglyoxal may be a key target for treating skeletal muscle atrophy. To this end, aerobic exercise may be a powerful tool for regulating methylglyoxal-induced skeletal muscle atrophy.

Diabetes is associated with an increased risk of muscle wasting/atrophy, which adversely affects quality of life. We hypothesized that long term supplementation of fish oil may have protective effects against sarcopenia or muscle atrophy in streptozotocin (STZ) and high-fat (HF) diet-induced diabetic rat model. Wistar rats at age of 7 weeks were injected with saline or STZ to induce hyperglycemia. After one week, they were fed on a normal control diet or HF diet with/without supplementation of fish oil for 18 weeks. Feeding diabetic rats with a fish oil-enriched diet alleviated body weight loss and the impaired glucose tolerance using OGTT test. Although fish oil did not improve the decreased muscle mass, the muscle atrophy induced by diabetes was attenuated by fish oil in gastrocnemius, soleus, tibialis anterior, and extensor digitorum longus muscles. Fish oil supplementation reversed the decreased expression of phospho (p)-AKT, pmTOR, and p-p70s6k, which are molecules related to protein synthesis. Besides, protein degradation-related signaling pathways were inhibited by fish oil, such as increasing p-FoxO1 and decreasing Atrogin-1 and MURF1 protein expression. Fish oil down-regulated the expression of autophagy-related molecules including ATG5, p62, and LC3B II/I ratio, which may result in less muscle atrophy. Inflammation-related signaling regulators including TNF-α, NF-κB, AGEs, and RAGE were suppressed by fish oil supplementation as well. Moreover, the down-regulated p-AMPKα, SIRT1, and PGC-1 in diabetic rats were counteracted by fish oil, which may improve mitochondrial function and further block FoxO action. These data suggest that long-term fish oil supplementation exerts protective effects against diabetes-induced muscle atrophy, which may in turn ameliorate insulin resistance and impaired glucose tolerance.