Molecular Mechanisms Of Muscle Atrophy Research Articles

Astragaloside IV Improves Muscle Atrophy by Modulating the Activity of UPS and ALP via Suppressing Oxidative Stress and Inflammation in Denervated Mice.

Peripheral nerve injury is common clinically and can lead to neuronal degeneration and atrophy and fibrosis of the target muscle. The molecular mechanisms of muscle atrophy induced by denervation are complex and not fully understood. Inflammation and oxidative stress play an important triggering role in denervated muscle atrophy. Astragaloside IV (ASIV), a monomeric compound purified from astragalus membranaceus, has antioxidant and anti-inflammatory properties. The aim of this study was to investigate the effect of ASIV on denervated muscle atrophy and its molecular mechanism, so as to provide a new potential therapeutic target for the prevention and treatment of denervated muscle atrophy. In this study, an ICR mouse model of muscle atrophy was generated through sciatic nerve dissection. We found that ASIV significantly inhibited the reduction of tibialis anterior muscle mass and muscle fiber cross-sectional area in denervated mice, reducing ROS and oxidative stress-related protein levels. Furthermore, ASIV inhibits the increase in inflammation-associated proteins and infiltration of inflammatory cells, protecting the denervated microvessels in skeletal muscle. We also found that ASIV reduced the expression levels of MAFbx, MuRF1 and FoxO3a, while decreasing the expression levels of autophagy-related proteins, it inhibited the activation of ubiquitin-proteasome and autophagy-lysosome hydrolysis systems and the slow-to-fast myofiber shift. Our results show that ASIV inhibits oxidative stress and inflammatory responses in skeletal muscle due to denervation, inhibits mitophagy and proteolysis, improves microvascular circulation and reverses the transition of muscle fiber types; Therefore, the process of skeletal muscle atrophy caused by denervation can be effectively delayed.

Ursolic Acid Induces Beneficial Changes in Skeletal Muscle mRNA Expression and Increases Exercise Participation and Performance in Dogs with Age-Related Muscle Atrophy.

Muscle atrophy and weakness are prevalent and debilitating conditions in dogs that cannot be reliably prevented or treated by current approaches. In non-canine species, the natural dietary compound ursolic acid inhibits molecular mechanisms of muscle atrophy, leading to improvements in muscle health. To begin to translate ursolic acid to canine health, we developed a novel ursolic acid dietary supplement for dogs and confirmed its safety and tolerability in dogs. We then conducted a randomized, placebo-controlled, proof-of-concept efficacy study in older beagles with age-related muscle atrophy, also known as sarcopenia. Animals received placebo or ursolic acid dietary supplements once a day for 60 days. To assess the study's primary outcome, we biopsied the quadriceps muscle and quantified atrophy-associated mRNA expression. Additionally, to determine whether the molecular effects of ursolic acid might have functional correlates consistent with improvements in muscle health, we assessed secondary outcomes of exercise participation and T-maze performance. Importantly, in canine skeletal muscle, ursolic acid inhibited numerous mRNA expression changes that are known to promote muscle atrophy and weakness. Furthermore, ursolic acid significantly improved exercise participation and T-maze performance. These findings identify ursolic acid as a natural dietary compound that inhibits molecular mechanisms of muscle atrophy and improves functional performance in dogs.

A Comprehensive Exercise (COMEX) Intervention to Optimize Exercise Participation for Improving Patient-Centered Outcomes and Physical Functioning in Patients Receiving Hemodialysis: Development and Pilot Testing

To address the need for an intradialytic exercise program that is easily delivered in clinical setting, engaging and scalable, we developed a novel COMprehensive EXercise (COMEX) program based on input from patients receiving hemodialysis (HD), dialysis staff members and nephrologists. The objective of this study was to determine the feasibility, safety, and acceptance of COMEX during HD. Single-arm prospective pilot feasibility study. Seventeen patients receiving in-center HD. Three-month participation in the COMEX program, which included video-based dialysis chair exercises (aerobic and resistance) integrated with educational and motivational components. Data on recruitment, adherence, safety and acceptability were collected. Additional assessments were performed to evaluate changes in physical functioning, patient-reported symptoms, and objectively measured sleep and physical activity. We also examined the feasibility of obtaining skeletal muscle biopsies and blood samples to explore molecular mechanisms of muscle atrophy and to assess platelet mitochondrial function and adaptation to exercise during HD. Thirteen of the 17 (76%) participants completed the 3-month intervention. The mean participant age was 63.6±15.1 years. In total, 46% of participants were males, and 55% were White. The mean body mass index was 38.7±11.6kg/m2. There were no reported adverse effects, and the adherence rate to exercise sessions was high with 88% of the sessions completed. Patient satisfaction was high, as 100% of the patients would recommend the program to other dialysis patients. It was feasible to collect data on physical functioning, patient-reported symptoms, and objective sleep and physical activity and to obtain muscle biopsies and blood samples. Small sample size, lack of an onsite exercise professional, and technological issues with telemedicine behavioral motivation. The COMEX intradialytic exercise intervention is safe and acceptable to patients, and outcome measures were feasible to obtain. Future studies should consider including exercise professionals to facilitate progression through a personalized exercise protocol. This work is supported by pilot award from P30 DK079307 (PI, Jhamb). ClinicalTrials.gov, NCT03055299. We tested a new COMprehensive EXercise (COMEX) program to deliver exercise during dialysis. This 3-month program included video-based dialysis chair exercises (aerobic and resistance) integrated with educational and motivational components. Our study shows COMEX was feasible, had high satisfaction and adherence, and was safe. It was feasible to collect data on physical functioning, patient-reported symptoms, and objective sleep and physical activity and to obtain muscle biopsies and blood samples. Future studies should consider including exercise professionals to facilitate progression through a personalized exercise protocol.

Pathophysiological basis of sarcopenia— a chronic complication of diabetes

The review considers the problem of sarcopenia, a muscle weakness and loss of mass, quality and strength of skeletal muscles, which often accompanies type 2 diabetes, especially in the elderly. Recently, sarcopenia has been considered as one of the complications of diabetes, which is associated with an increase in the frequency of cardiovascular complications, the need for hospitalization, and patient mortality. The molecular mechanisms of muscle atrophy in sarcopenia are associated with a violation of the anabolic-catabolic balance in muscles and their energy supply, fatty infiltration and shifts in proteostasis (decreasing the synthesis of muscle proteins and increasing their degradation), mitochondrial dysfunction. Insulin resistance, oxidative stress, accumulation of abdominal and ectopic fat, local inflammation play a key role in the pathogenesis of both sarcopenia and dysmetabolic diabetic complications, i.e., there is a bidirectional relationship between these pathological conditions, which mutually reinforce each other’s negative consequences. According to clinical observations, the risk of sarcopenia in patients with diabetes is 3–4 times higher than in people without diabetes, while the presence of sarcopenia increases the risk of reduced work capacity, disability, mortality, and worsening of diabetes control. These data indicate the feasibility of screening for signs of sarcopenia in patients with type 2 diabetes, especially in the older age group, using dynamic tests, as well as bone monitoring, to prevent the risk of falls and fractures. Antidiabetic therapy for such patients should include drugs that help preserve muscle and bone tissue (have an anabolic effect), do not increase the risk of hypoglycemia and gastrointestinal disorders. According to the literature, the safest preparations include the biguanide metformin, dipeptidyl peptidase inhibitors, and insulin. Sulfonylurea derivatives, thiazolidinediones, glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter-2 inhibitors are not recommended, as they can cause undesirable effects in weakened elderly people. Timely diagnosis of sarcopenia is important to prevent the deterioration of muscle function (through the rehabilitation of the musculoskeletal system using adaptive physical exercises and diet modification) and to improve the quality of life of patients with type 2 diabetes. In turn, improving the prevention and treatment of diabetes in the early stages can also help prevent the development of sarcopenia and its complications.

Diabetic Muscular Atrophy: Molecular Mechanisms and Promising Therapies

Diabetes mellitus (DM) is a typical chronic disease that can be divided into 2 types, dependent on insulin deficiency or insulin resistance. Incidences of diabetic complications gradually increase as the disease progresses. Studies in diabetes complications have mostly focused on kidney and cardiovascular diseases, as well as neuropathy. However, DM can also cause skeletal muscle atrophy. Diabetic muscular atrophy is an unrecognized diabetic complication that can lead to quadriplegia in severe cases, seriously impacting patients’ quality of life. In this review, we first identify the main molecular mechanisms of muscle atrophy from the aspects of protein degradation and synthesis signaling pathways. Then, we discuss the molecular regulatory mechanisms of diabetic muscular atrophy, and outline potential drugs and treatments in terms of insulin resistance, insulin deficiency, inflammation, oxidative stress, glucocorticoids, and other factors. It is worth noting that inflammation and oxidative stress are closely related to insulin resistance and insulin deficiency in diabetic muscular atrophy. Regulating inflammation and oxidative stress may represent another very important way to treat diabetic muscular atrophy, in addition to controlling insulin signaling. Understanding the molecular regulatory mechanism of diabetic muscular atrophy could help to reveal new treatment strategies.

Bioinformatic analysis of the gene expression profile in muscle atrophy after spinal cord injury

Spinal cord injury (SCI) is often accompanied by muscle atrophy; however, its underlying mechanisms remain unclear. Here, the molecular mechanisms of muscle atrophy following SCI were investigated. The GSE45550 gene expression profile of control (before SCI) and experimental (14 days following SCI) groups, consisting of Sprague–Dawley rat soleus muscle (n = 6 per group), was downloaded from the Gene Expression Omnibus database, and then differentially expressed gene (DEG) identification and Gene Ontology, pathway, pathway network, and gene signal network analyses were performed. A total of 925 differentially expressed genes, 149 biological processes, and 55 pathways were screened. In the pathway network analysis, the 10 most important pathways were citrate cycle (TCA cycle), pyruvate metabolism, MAPK signalling pathway, fatty acid degradation, propanoate metabolism, apoptosis, focal adhesion, synthesis and degradation of ketone bodies, Wnt signalling, and cancer pathways. In the gene signal network analysis, the 10 most important genes were Acat1, Acadvl, Acaa2, Hadhb, Acss1, Oxct1, Hadha, Hadh, Acaca, and Cpt1b. Thus, we screened the key genes and pathways that may be involved in muscle atrophy after SCI and provided support for finding valuable markers for this disease.

Role of Mitochondrial Calcium in the Maintenance of Skeletal Muscle Homeostasis

PV is a member of the EF-hand Ca2+-binding family of proteins, expressed in fast-twitch muscle fibers where, acting as a soluble cytoplasmic Ca2+ buffer, contributes to musclerelaxation by removing Ca2+ from the cytosol and facilitating its transport back to the SR. Furthermore, PV is one of the most downregulated “atrogenes”, the family of genes commonly up- and downregulated in both systemic and disuse-induced muscle atrophy. We exploited the murine strain lacking PV (PV-/-) to explore the link between PV function as Ca2+ buffer and as determinant of muscle trophism. First, we confirmed that PV expression is downregulated in denervated muscles and, surprisingly, we found a trend to a lower muscle atrophy in PV-/- than in wild type (WT) mice. Then, by acutely silencing and overexpressing PV in adult muscles of WT mice, we discovered that downregulation was accompanied by hypertrophy and upregulation by atrophy. The lack of PV had a minor impact on sarcoplasmic reticulum and affected the kinetics but not the amplitude of the cytosolic Ca2+ transients. In contrast, PV ablation was associated with an increased Ca2+ uptake in mitochondria, partly supported by MCU increased expression and accompanied by increased mitochondria size and number. Intriguingly, MCU silencing abolished the hypertrophic effect of PV ablation, suggesting a mitochondrial Ca2+-dependent mechanism of control of muscle trophism. This was corroborated by the enhanced expression of the mitochondrial Ca2+-dependent PGC-1α4 that promotes skeletal muscle hypertrophy. MCU silencing prevented increase of PGC-1αα4 expression and PGC-1α4 silencing prevented muscle fiber hypertrophy. These data reveal a novel role of PV that links the control of cytosolic Ca2+ concentration to mitochondrial adaptations, ultimately leading to muscle mass regulation. We believe that our results further underline that the mitochondrial pathway and its regulation are of utmost importance to uncover the molecular mechanisms of muscle atrophy.

Skeletal Muscle Atrophy: Discovery of Mechanisms and Potential Therapies.

Skeletal muscle atrophy proceeds through a complex molecular signaling network that is just beginning to be understood. Here, we discuss examples of recently identified molecular mechanisms of muscle atrophy and how they highlight an immense need and opportunity for focused biochemical investigations and further unbiased discovery work.

Physiology in Perspective: The Dilemma of Muscle Weakness.

Physiology in Perspective: The Dilemma of Muscle Weakness.

Identification and Characterization of Protein Phosphatase Methylesterase 1 (Ppme1) in Skeletal Muscle

Skeletal muscle atrophy results from a range of physiological conditions, including immobilization, denervation, glucocorticoid treatment, cancer, and aging. To provide a better understanding of the pathway of skeletal muscle atrophy, a previous study conducted a microarray analysis of muscle from mice undergoing neurogenic atrophy in response to denervation as well as dexamethasone exposure. The data generated from this microarray identified a suite of several hundred predicted genes that displayed differential expression under conditions of muscle wasting, including protein phosphatase methylesterase‐1 (Ppme1). The Ppme1 gene was observed to be transcriptionally upregulated in response to neurogenic skeletal muscle atrophy (i.e. denervation). To confirm that Ppme1 is expressed in muscle, qPCR was performed using RNA isolated from cultured muscle cells at different stages of proliferation and differentiation and expression was found to be relatively constant in both proliferating and differentiated cells. In addition, Ppme1 protein levels were analyzed by Western blot analysis and found to be expressed at a constant level at different time points throughout muscle cell proliferation and differentiation. Additionally, the cDNA of Ppme1 was fused in frame with GFP and subcellular localization was analyzed by confocal fluorescent microscopy in proliferating myoblasts. To assess the transcriptional activity of the Ppme1 gene, fragments of the promoter were cloned, fused to a reporter gene, transfected into C2C12 cells, and found to be highly transcriptionally active. Interestingly, the Ppme1 reporter gene constructs were not significantly affected by ectopic expression of myogenic regulatory facts such as MyoD1 and myogenin. Finally, mouse myoblast cells treated with an inhibitor of Ppme1 displayed reduced AP‐1 reporter activity as well as delayed muscle cell differentiation. The results presented here help contribute new insights into the molecular mechanisms of muscle atrophy and may provide a better understanding of the genome‐wide transcriptional changes and cellular events that occur during skeletal muscle wasting.Support or Funding InformationThe work was support by University of North Florida Transformational Learning Opportunity grants and a University of North Florida Foundation Board Grant to D.W.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Cellular and molecular mechanisms of muscle atrophy

Skeletal muscle is a plastic organ that is maintained by multiple pathways regulating cell and protein turnover. During muscle atrophy, proteolytic systems are activated, and contractile proteins and organelles are removed, resulting in the shrinkage of muscle fibers. Excessive loss of muscle mass is associated with poor prognosis in several diseases, including myopathies and muscular dystrophies, as well as in systemic disorders such as cancer, diabetes, sepsis and heart failure. Muscle loss also occurs during aging. In this paper, we review the key mechanisms that regulate the turnover of contractile proteins and organelles in muscle tissue, and discuss how impairments in these mechanisms can contribute to muscle atrophy. We also discuss how protein synthesis and degradation are coordinately regulated by signaling pathways that are influenced by mechanical stress, physical activity, and the availability of nutrients and growth factors. Understanding how these pathways regulate muscle mass will provide new therapeutic targets for the prevention and treatment of muscle atrophy in metabolic and neuromuscular diseases.

Stress-induced Skeletal Muscle Gadd45a Expression Reprograms Myonuclei and Causes Muscle Atrophy

Diverse stresses including starvation and muscle disuse cause skeletal muscle atrophy. However, the molecular mechanisms of muscle atrophy are complex and not well understood. Here, we demonstrate that growth arrest and DNA damage-inducible 45a protein (Gadd45a) is a critical mediator of muscle atrophy. We identified Gadd45a through an unbiased search for potential downstream mediators of the stress-inducible, pro-atrophy transcription factor ATF4. We show that Gadd45a is required for skeletal muscle atrophy induced by three distinct skeletal muscle stresses: fasting, muscle immobilization, and muscle denervation. Conversely, forced expression of Gadd45a in muscle or cultured myotubes induces atrophy in the absence of upstream stress. We show that muscle-specific ATF4 knock-out mice have a reduced capacity to induce Gadd45a mRNA in response to stress, and as a result, they undergo less atrophy in response to fasting or muscle immobilization. Interestingly, Gadd45a is a myonuclear protein that induces myonuclear remodeling and a comprehensive program for muscle atrophy. Gadd45a represses genes involved in anabolic signaling and energy production, and it induces pro-atrophy genes. As a result, Gadd45a reduces multiple barriers to muscle atrophy (including PGC-1α, Akt activity, and protein synthesis) and stimulates pro-atrophy mechanisms (including autophagy and caspase-mediated proteolysis). These results elucidate a critical stress-induced pathway that reprograms muscle gene expression to cause atrophy.

Exercise Training Attenuates MuRF-1 Expression in the Skeletal Muscle of Patients With Chronic Heart Failure Independent of Age

Background— Muscle wasting occurs in both chronic heart failure (CHF) and normal aging and contributes to exercise intolerance and increased morbidity/mortality. However, the molecular mechanisms of muscle atrophy in CHF and their interaction with aging are still largely unknown. We therefore measured the activation of the ubiquitin-proteasome system and the lysosomal pathway of intracellular proteolysis in muscle biopsies of CHF patients and healthy controls in two age strata and assessed the age-dependent effects of a 4-week endurance training program on the catabolic-anabolic balance. Methods and Results— Sixty CHF patients (30 patients aged ≤55 years, mean age 46±5 years; 30 patients aged ≥65 years, mean age 72±5 years) and 60 healthy controls (30 subjects aged ≤55 years, mean age 50±5 years; 30 subjects aged ≥65 years, mean age 72±4 years) were randomized to 4 weeks of supervised endurance training or to a control group. Before and after the intervention, vastus lateralis muscle biopsies were obtained. The expressions of cathepsin-L and the muscle-specific E3 ligases MuRF-1 and MAFbx were measured by real-time polymerase chain reaction and confirmed by Western blot. At baseline, MuRF-1 expression was significantly higher in CHF patients versus healthy controls (mRNA: 624±59 versus 401±25 relative units; P =0.007). After 4 weeks of exercise training, MuRF-1 mRNA expression was reduced by −32.8% ( P =0.02) in CHF patients aged ≤55 years and by −37.0% ( P <0.05) in CHF patients aged ≥65 years. Conclusions— MuRF-1, a component of the ubiquitin-proteasome system involved in muscle proteolysis, is increased in the skeletal muscle of patients with heart failure. Exercise training results in reduced MuRF-1 levels, suggesting that it blocks ubiquitin-proteasome system activation and does so in both younger and older CHF patients. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00176319.

A Mouse Model of Massive Rotator Cuff Tears

Rotator cuff tears are the most common tendon injury seen in orthopaedic patients. Muscle atrophy and fatty infiltration in rotator cuff muscles are considered among the key factors responsible for the failure of attempted repair of a massive rotator cuff tear. However, the pathophysiology of rotator cuff muscle atrophy and fatty infiltration remains largely unknown, partly because of the lack of appropriate small animal models. The goal of this study was to develop a mouse model of muscle atrophy and fatty infiltration after a rotator cuff tear. We also sought to study the role of denervation on muscle atrophy and fatty infiltration after a rotator cuff tear. Adult wild-type FVB/N mice were randomly divided into three groups. Mice in different groups received unilateral complete supraspinatus and infraspinatus tendon transection, suprascapular nerve transection, or both procedures. Sham surgery was performed on the contralateral shoulder to serve as a control. Mice were killed twelve weeks after surgery. Histological analysis and high-resolution magnetic resonance imaging were used to evaluate muscle atrophy and fat infiltration after a rotator cuff tear. Significant and consistent muscle atrophy and fatty infiltration were observed in the rotator cuff muscles after rotator cuff tendon transection. We further found that denervation significantly increases the amount of muscle atrophy and fatty infiltration after a rotator cuff tear. We successfully developed a novel mouse model of a massive rotator cuff tear, which simulates major pathological changes, including muscle atrophy and fatty infiltration after massive rotator cuff tears seen in patients.

Molecular mechanism of unloading-mediated muscle atrophy and development of its countermeasures

The ubiquitin ligase Cbl-b plays a major role in skeletal muscle atrophy induced by unloading [1]. The mechanism of Cbl-b-induced muscle atrophy is unique in that it does not appear to involve the degradation of structural components of the muscle, but rather it impairs muscular trophic signals in response to unloading conditions. Recent studies on the molecular mechanisms of muscle atrophy have focused on the role of IGF-1/PI3K/Akt-1 signaling cascade as a vital pathway in the regulation of the balance between hypertrophy and atrophy [2,3]. These studies indicate that under muscle wasting conditions, such as disuse, diabetes and fasting, decreased IGF-1/PI3K/Akt-1 signaling augments the expression of atrogin-1, resulting in muscle atrophy. However, these studies did not address the mechanisms of unloading-induced impairment of growth factor signaling. In the present study, we found that under both in vitro and in vivo experimental conditions, Cbl-b ubiquitinated and induced specific degradation of IRS-1, a key intermediate of skeletal muscle growth regulated by IGF-1/insulin and growth hormone, resulting in inactivation of Akt-1. Inactivation of Akt-1 led to upregulation of atrogin-1 through dephosphorylation (activation) of FOXO3, as well as reduced mitogen response, in skeletal muscle. Thus, activation of Cbl-b may be an important mechanism underlying the failure of atrophic muscle to respond to growth factor-based treatments such as IGF-1 (Figure ​(Figure11). Figure 1 Possible mechanism of unloading-mediated muscle atrophy.

Molecular Mechanisms in Aging and Current Strategies to Counteract Sarcopenia

Sarcopenia, the progressive loss of muscle mass with age, is characterized by a deterioration of muscle quantity and quality leading to a gradual slowing of movement and a decline in strength and power. Sarcopenia is a highly significant public health problem. Since these age-related changes in skeletal muscle are largely attributed to various molecular mediators affecting fiber size, mitochondrial homeostatis, and apoptosis, the mechanisms responsible for these deleterious changes present numerous therapeutic targets for drug discovery. We and other researchers demonstrated that a disruption of Akt-mTOR and RhoA-SRF signaling but not Atrogin-1 or MuRF1 contributes to sarcopenia. In addition, sarcopenia seems to include a marked loss of fibers attributable to apoptosis. This review deals with molecular mechanisms of muscle atrophy and provides an update on current strategies (resistance training, myostatin inhibition, treatment with amino acids or testosterone, calorie restriction, etc) for counteracting this loss. Resistance training in combination with amino acid-containing nutrition would be the best candidate to attenuate, prevent, or ultimately reverse age-related muscle wasting and weakness.

"Myo Lab": A JAXA Cell Biology Experiment in "Kibo (JEM)" of the International Space Station

Skeletal muscle atrophy is an often-unavoidable response to a prolonged lack of muscle use or spaceflight (referred to as unloading), and presents a particular challenge for astronauts during spaceflight. An increased understanding of the molecular mechanisms of muscle atrophy may lead to the development of effective therapies to combat this widespread condition. In this project, we aim to elucidate the molecular mechanisms of microgravity-induced skeletal muscle atrophy, especially physiological relevance of Cbl-b ubiquitin ligase. Japanese experimental module (JEM), Kibo, in International Space Station has been constructed until June, 2009. This enables us to perform cell culture experiment, which is an easy system to observe direct effects of microgravity on the cell, in space for a long term. This project is called Myo Lab, which means Laboratory for Skeletal Muscle. This decal images our dream (space shuttle) that flight beyond Earth forward to Kibo. In addition, the flame from shuttle means skeletal muscle.

Muscle Atrophy and Hypertrophy Signaling in Patients with Chronic Obstructive Pulmonary Disease

The molecular mechanisms of muscle atrophy in chronic obstructive pulmonary disease (COPD) are poorly understood. In wasted animals, muscle mass is regulated by several AKT-related signaling pathways. To measure the protein expression of AKT, forkhead box class O (FoxO)-1 and -3, atrogin-1, the phosphophrylated form of AKT, p70(S6K) glycogen synthase kinase-3beta (GSK-3beta), eukaryotic translation initiation factor 4E binding protein-1 (4E-BP1), and the mRNA expression of atrogin-1, muscle ring finger (MuRF) protein 1, and FoxO-1 and -3 in the quadriceps of 12 patients with COPD with muscle atrophy and 10 healthy control subjects. Five patients with COPD with preserved muscle mass were subsequently recruited and were compared with six patients with low muscle mass. Protein contents and mRNA expression were measured by Western blot and quantitative polymerase chain reaction, respectively. The levels of atrogin-1 and MuRF1 mRNA, and of phosphorylated AKT and 4E-BP1 and FoxO-1 proteins, were increased in patients with COPD with muscle atrophy compared with healthy control subjects, whereas atrogin-1, p70(S6K), GSK-3beta, and FoxO-3 protein levels were similar. Patients with COPD with muscle atrophy showed an increased expression of p70(S6K), GSK-3beta, and 4E-BP1 compared with patients with COPD with preserved muscle mass. An increase in atrogin-1 and MuRF1 mRNA and FoxO-1 protein content was observed in the quadriceps of patients with COPD. The transcriptional regulation of atrogin-1 and MuRF1 may occur via FoxO-1, but independently of AKT. The overexpression of the muscle hypertrophic signaling pathways found in patients with COPD with muscle atrophy could represent an attempt to restore muscle mass.

Modifying muscle mass – the endocrine perspective

This review describes the major hormonal factors that determine the balance between human skeletal muscle anabolism and catabolism in health and disease, with specific reference to age-related muscle loss (sarcopenia). The molecular mechanisms associated with muscle hypertrophy are described, and the central role of the satellite cell highlighted. The biological dynamics of satellite cells, varying between states of quiescence, proliferation and differentiation are strongly influenced by local endocrine factors. The molecular mechanisms of muscle atrophy are examined focussing on the causes of sarcopenia and associations with systemic medical disorders. In addition, evidence is provided that the mechanisms of atrophy and hypertrophy are unlikely to be simple opposites. Novel endocrine mechanisms underpinning mechano-transduction include IGF-I subtypes that may differentiate between endocrine and mechanical signals; their interaction with classical endocrine factors is an active area of translational research. Recently acquired knowledge on the mechanism of anabolic effects of androgens is also reviewed. The increasingly recognised role of myostatin, a negative regulator of muscle function, is described, as well as its potential as a therapeutic target. Strategies to counter age-related sarcopenia thus represent an exciting field of future investigation.

Towards an understanding of molecular mechanisms of muscle atrophy: editorial comment

Diabetes and Nutrition Unit, University of Louvain, Brussels, Belgium Correspondence to Jean-Paul Thissen, MD, PhD, Diabetes and Nutrition Unit, University of Louvain, Avenue Hippocrate 54, B-1200 Brussels, Belgium Tel: +32 2 764 54 69; fax: +32 2 764 54 18 e-mail: [email protected]