Skeletal Muscle Disease Research Articles

Lean tissue mass measurements by dual-energy X-ray absorptiometry and associations with strength and functional outcome measures in facioscapulohumeral muscular dystrophy

Facioscapulohumeral muscular dystrophy (FSHD) is a slowly progressive disease of skeletal muscle. Dual energy X-ray absorptiometry (DEXA) is a widely available, cost-effective and sensitive technique for measuring whole body and regional lean tissue mass and has been used in prior clinical trials in neuromuscular diseases. The Clinical Trial Readiness to Solve Barriers to Drug Development in FSHD (ReSolve) study is a prospective, longitudinal, observational multisite study. We obtained concurrent DEXA scans and functional outcome measurements in 185 patients with FSHD at the baseline visit. We determined the associations between lean tissue mass in the upper and lower extremities and corresponding clinical outcome measures. There were moderate correlations between upper and lower extremity lean tissue mass and their corresponding strengths and function. Lean tissue mass obtained by DEXA scan may be useful as a biomarker in future clinical trials in FSHD.

MDFI regulates fast-to-slow muscle fiber type transformation via the calcium signaling pathway

Muscle fiber is the basic unit of skeletal muscle with strong self-adaptability, and its type is closely related to meat quality. Myod family inhibitor (Mdfi) has the function of regulating myogenic regulatory factors during cell differentiation, but how Mdfi regulates muscle fiber type transformation in myoblasts is still unclear. In the present study, we constructed overexpressing and interfering with Mdfi C2C12 cell models by lipofection. The immunofluorescence, quantitative real-time PCR (qPCR), and western blot results show that the elevated MDFI promoted mitochondrial biogenesis, aerobic metabolism and the calcium level by activating CaMKK2 and AMPK phosphorylation and then stimulated the conversion of C2C12 cells from fast glycolytic to slow oxidative type. In addition, after inhibiting IP3R and RYR channels, the higher MDFI reversed the blockage of calcium release from the endoplasmic reticulum by calcium channel receptor inhibitors and increased intracellular calcium levels. Therefore, we propose that the higher MDFI promotes muscle fiber types conversion through the calcium signaling pathway. These findings further broaden our understanding of the regulatory mechanism of MDFI in muscle fiber type transformation. Furthermore, our results suggest potential therapeutic targets for skeletal muscle and metabolic-related diseases.

Modern guidelines for the diagnosis of sarcopenia

Sarcopenia is a progressive generalized skeletal muscle disease characterized by loss of muscle mass and decreased muscle function with an increased risk of adverse events. For a long time, loss of muscle mass and function has been studied as a clinical symptom in severe diseases and conditions in oncology, endocrinology, rheumatology, and a number of other systemic diseases. However, with the increase in life expectancy and aging of the population, sarcopenia, as an independent age-associated disease, comes into general medical practice and makes a significant contribution to the rates of disability and mortality. To date, several definitions of sarcopenia, screening methods and diagnostic criteria for this disease have been proposed by various international research groups. This review presents evolution of definitions and diagnostic criteria for sarcopenia and severe sarcopenia. Changes in the algorithm for sarcopenia diagnostics according to the latest recommendations of the European Working Group on Sarcopenia for Older People (EWGSOP) second revision, published in 2018 (EWGSOP2), as well as the results of the consensus of the American Geriatric Society and the International Group on study of sarcopenia. This review summarizes practical issues regarding methods for assessing muscle mass, muscle strength and skeletal muscle function, diagnostics threshold for sarcopenia from leading international research groups, as well as the results of researchers’ work on adapting tests for assessing sarcopenia in Russia.

Molecular therapies: present and future in neuromuscular diseases

The possibilities in the field of molecular therapies of neuromuscular diseases have rapidly developed in recent years. First compounds are already available in clinical practice and numerous other substances are in advanced phases of clinical trials. This article gives an exemplary overview of the current state of clinical research in molecular therapies of neuromuscular diseases. It also gives a view into the near future of the clinical application, including the challenges. Using Duchenne muscular dystrophy (DMD) and myotubular myopathy as examples, the principles of gene addition in monogenetic skeletal muscle diseases, which are already manifested in childhood are described. In addition to initial successes, the challenges and setbacks hindering the approval and regular clinical application of further compounds are demonstrated. Furthermore, the state of current clinical research in Becker-Kiener muscular dystrophy (BMD) and the numerous forms of limb-girdle muscular dystrophy (LGMD) are summarized. Numerous new therapeutic approaches and acorresponding outlook are also shown for facioscapulohumeral muscular dystrophy (FSHD), Pompe disease, and myotonic dystrophy. Clinical research in the field of molecular therapy of neuromuscular diseases is one of the pacesetters of modern precision medicine; however, challenges need to be seen, jointly addressed and overcome in the future.

Broadband Electrical Spectroscopy to Distinguish Single-Cell Ca2+ Changes Due to Ionomycin Treatment in a Skeletal Muscle Cell Line.

Many skeletal muscle diseases such as muscular dystrophy, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and sarcopenia share the dysregulation of calcium (Ca2+) as a key mechanism of disease at a cellular level. Cytosolic concentrations of Ca2+ can signal dysregulation in organelles including the mitochondria, nucleus, and sarcoplasmic reticulum in skeletal muscle. In this work, a treatment is applied to mimic the Ca2+ increase associated with these atrophy-related disease states, and broadband impedance measurements are taken for single cells with and without this treatment using a microfluidic device. The resulting impedance measurements are fitted using a single-shell circuit simulation to show calculated electrical dielectric property contributions based on these Ca2+ changes. From this, similar distributions were seen in the Ca2+ from fluorescence measurements and the distribution of the S-parameter at a single frequency, identifying Ca2+ as the main contributor to the electrical differences being identified. Extracted dielectric parameters also showed different distribution patterns between the untreated and ionomycin-treated groups; however, the overall electrical parameters suggest the impact of Ca2+-induced changes at a wider range of frequencies.

Phase 1/2 Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamic Effects of AOC 1020 Administered Intravenously to Adult Patients with Facioscapulohumeral Muscular Dystrophy (FORTITUDE) Trial Design (P3-8.007)

Phase 1/2 Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamic Effects of AOC 1020 Administered Intravenously to Adult Patients with Facioscapulohumeral Muscular Dystrophy (FORTITUDE) Trial Design (P3-8.007)

Brody myopathy associated with novel compound heterozygous ATP2A1 mutations (P6-8.015)

<h3>Objective:</h3> To describe a case of presumed Brody myopathy associated with novel compound heterozygous ATP2A1 mutations. <h3>Background:</h3> Brody myopathy is a rare autosomal recessive skeletal muscle disease characterized by exertional muscle cramps, weakness, and/or rhabdomyolysis associated with clinical myotonia. <h3>Design/Methods:</h3> N/A <h3>Results:</h3> A 19-year-old man with normal development and motor milestones presented to neuromuscular clinic after two episodes of exercise-induced muscle weakness and rhabdomyolysis in the past 6-months. Peak creatinine phosphokinase (CPK) was &gt;63,000 units/L and he quickly returned to baseline after each episode with intravenous fluids and supportive care. Remaining initial testing including serum total carnitine and acylcarnitine levels, and urine organic acid levels, were normal. He provided additional history of progressive difficulty relaxing leg and handgrip muscles after exertion since childhood, and multiple episodes of asymptomatic dark-colored urine provoked by strenuous exercise over the past two years. Physical examination showed bilateral grip and percussion myotonia with otherwise normal muscle bulk, strength, and remaining neurologic examination. Electromyography was normal. Genetic testing including myotonic dystrophy types 1 and 2, Pompe disease, and non-dystrophic myotonic disorders was notable for compound heterozygous ATP2A1 gene c.2032C&gt;T (p.Arg678Cys) and c.2176G&gt;A (p.Val726Met) variants of uncertain significance. Separate pathogenic mutations in this gene cause Brody myopathy, a non-dystrophic myotonic disorder characterized by exertional rhabdomyolysis. The patient is presumed to have Brody myopathy due to novel compound heterozygous ATP2A1 mutations. <h3>Conclusions:</h3> Brody myopathy should be considered in individuals presenting with muscle cramps, clinical myotonia, and exertional rhabdomyolysis. Clinical features and electromyographic findings are milder than myotonic dystrophies, Pompe disease, and typical non-dystrophic myotonic disorders. Genetic testing including ATP2A1 gene sequencing aids diagnosis. Management is supportive, although individuals should be aware of a 5% association with malignant hyperthermia-like episodes after exposure to volatile anesthetics. <b>Disclosure:</b> Dr. Walia has nothing to disclose. Dr. Su has nothing to disclose.

The crosstalk between BAT thermogenesis and skeletal muscle dysfunction.

Metabolic defects increase the risk of skeletal muscle diseases, and muscle impairment might worsen metabolic disruption, leading to a vicious cycle. Both brown adipose tissue (BAT) and skeletal muscle play important roles in non-shivering thermogenesis to regulate energy homeostasis. BAT regulates body temperature, systemic metabolism, and seretion of batokines that have positive or negative impacts on skeletal muscle. Conversely, muscle can secrete myokines that regulate BAT function. This review explained the crosstalk between BAT and skeletal muscle, and then discussed the batokines and highlighted their impact on skeletal muscle under physiological conditions. BAT is now considered a potential therapeutic target for obesity and diabetes treatment. Moreover, manipulation of BAT may be an attractive approach for the treatment of muscle weakness by correcting metabolic deficits. Therefore, exploring BAT as a potential treatment for sarcopenia could be a promising avenue for future research.

3D bioprinted functional skeletal muscle models have potential applications for studies of muscle wasting in cancer cachexia

Acquired muscle diseases such as cancer cachexia are responsible for the poor prognosis of many patients suffering from cancer. In vitro models are needed to study the underlying mechanisms of those pathologies. Extrusion bioprinting is an emerging tool to emulate the aligned architecture of fibers while implementing additive manufacturing techniques in tissue engineering. However, designing bioinks that reconcile the rheological needs of bioprinting and the biological requirements of muscle tissue is a challenging matter. Here we formulate a biomaterial with dual crosslinking to modulate the physical properties of bioprinted models. We design 3D bioprinted muscle models that resemble the mechanical properties of native tissue and show improved proliferation and high maturation of differentiated myotubes suggesting that the GelMA-AlgMA-Fibrin biomaterial possesses myogenic properties. The electrical stimulation of the 3D model confirmed the contractile capability of the tissue and enhanced the formation of sarcomeres. Regarding the functionality of the models, they served as platforms to recapitulate skeletal muscle diseases such as muscle wasting produced by cancer cachexia. The genetic expression of 3D models demonstrated a better resemblance to the muscular biopsies of cachectic mouse models. Altogether, this biomaterial is aimed to fabricate manipulable skeletal muscle in vitro models in a non-costly, fast and feasible manner.

Roles and heterogeneity of mesenchymal progenitors in muscle homeostasis, hypertrophy, and disease.

Skeletal muscle is mainly composed of multinucleated cells called myofibers, and has excellent regenerative and adaptive abilities. These abilities are granted by muscle satellite cells (MuSCs), which are anatomically defined cells located between myofibers and basal lamina. In addition to myofibers and MuSCs, skeletal muscle contains several types of cells located in interstitial areas, such as mesenchymal progenitors. These cells are positive for platelet-derived growth factor receptor alpha and are called fibro/adipogenic progenitors (FAPs) or mesenchymal stromal cells. Although mesenchymal progenitors were originally identified as the causative cells of ectopic fat accumulation in skeletal muscles, recent studies have shed light on their beneficial roles in homeostasis, regeneration, and hypertrophy. Furthermore, the heterogeneity of mesenchymal progenitors is of great interest in understanding skeletal muscle development, homeostasis, regeneration, aging, and diseases. In this concise review, we summarize recent findings on the physiological roles of mesenchymal progenitors and their heterogeneity and discuss the remaining critical concerns.

Nuclear mechanosignaling in striated muscle diseases.

Mechanosignaling describes processes by which biomechanical stimuli are transduced into cellular responses. External biophysical forces can be transmitted via structural protein networks that span from the cellular membrane to the cytoskeleton and the nucleus, where they can regulate gene expression through a series of biomechanical and/or biochemical mechanosensitive mechanisms, including chromatin remodeling, translocation of transcriptional regulators, and epigenetic factors. Striated muscle cells, including cardiac and skeletal muscle myocytes, utilize these nuclear mechanosignaling mechanisms to respond to changes in their intracellular and extracellular mechanical environment and mediate gene expression and cell remodeling. In this brief review, we highlight and discuss recent experimental work focused on the pathway of biomechanical stimulus propagation at the nucleus-cytoskeleton interface of striated muscles, and the mechanisms by which these pathways regulate gene regulation, muscle structure, and function. Furthermore, we discuss nuclear protein mutations that affect mechanosignaling function in human and animal models of cardiomyopathy. Furthermore, current open questions and future challenges in investigating striated muscle nuclear mechanosignaling are further discussed.

Preparation of 3D Decellularized Matrices from Fetal Mouse Skeletal Muscle for Cell Culture.

The extracellular matrix (ECM) plays a crucial role in providing structural support for cells and conveying signals that are important for various cellular processes. Two-dimensional (2D) cell culture models oversimplify the complex interactions between cells and the ECM, as the lack of a complete three-dimensional (3D) support can alter cell behavior, making them inadequate for understanding in vivo processes. Deficiencies in ECM composition and cell-ECM interactions are important contributors to a variety of different diseases. One example is LAMA2-congenital muscular dystrophy (LAMA2-CMD), where the absence or reduction of functional laminin 211 and 221 can lead to severe hypotony, detectable at or soon after birth. Previous work using a mouse model of the disease suggests that its onset occurs during fetal myogenesis. The present study aimed to develop a 3D in vitro model permitting the study of the interactions between muscle cells and the fetal muscle ECM, mimicking the native microenvironment. This protocol uses deep back muscles dissected from E18.5 mouse fetuses, treated with a hypotonic buffer, an anionic detergent, and DNase. The resultant decellularized matrices (dECMs) retained all ECM proteins tested (laminin α2, total laminins, fibronectin, collagen I, and collagen IV) compared to the native tissue. When C2C12 myoblasts were seeded on top of these dECMs, they penetrated and colonized the dECMs, which supported their proliferation and differentiation. Furthermore, the C2C12 cells produced ECM proteins, contributing to the remodeling of their niche within the dECMs. The establishment of this in vitro platform provides a new promising approach to unravel the processes involved in the onset of LAMA2-CMD, and has the potential to be adapted to other skeletal muscle diseases where deficiencies in communication between the ECM and skeletal muscle cells contribute to disease progression.

Sarcoplasmic Reticulum Ca2+ Buffer Proteins: A Focus on the Yet-To-Be-Explored Role of Sarcalumenin in Skeletal Muscle Health and Disease.

Sarcalumenin (SAR) is a luminal Ca2+ buffer protein with high capacity but low affinity for calcium binding found predominantly in the longitudinal sarcoplasmic reticulum (SR) of fast- and slow-twitch skeletal muscles and the heart. Together with other luminal Ca2+ buffer proteins, SAR plays a critical role in modulation of Ca2+ uptake and Ca2+ release during excitation-contraction coupling in muscle fibers. SAR appears to be important in a wide range of other physiological functions, such as Sarco-Endoplasmic Reticulum Calcium ATPase (SERCA) stabilization, Store-Operated-Calcium-Entry (SOCE) mechanisms, muscle fatigue resistance and muscle development. The function and structural features of SAR are very similar to those of calsequestrin (CSQ), the most abundant and well-characterized Ca2+ buffer protein of junctional SR. Despite the structural and functional similarity, very few targeted studies are available in the literature. The present review provides an overview of the role of SAR in skeletal muscle physiology, as well as of its possible involvement and dysfunction in muscle wasting disorders, in order to summarize the current knowledge on SAR and drive attention to this important but still underinvestigated/neglected protein.

Variants in DTNA cause a mild, dominantly inherited muscular dystrophy.

DTNA encodes α-dystrobrevin, a component of the macromolecular dystrophin-glycoprotein complex (DGC) that binds to dystrophin/utrophin and α-syntrophin. Mice lacking α-dystrobrevin have a muscular dystrophy phenotype, but variants in DTNA have not previously been associated with human skeletal muscle disease. We present 12 individuals from four unrelated families with two different monoallelic DTNA variants affecting the coiled-coil domain of α-dystrobrevin. The five affected individuals from family A harbor a c.1585G > A; p.Glu529Lys variant, while the recurrent c.1567_1587del; p.Gln523_Glu529del DTNA variant was identified in the other three families (family B: four affected individuals, family C: one affected individual, and family D: two affected individuals). Myalgia and exercise intolerance, with variable ages of onset, were reported in 10 of 12 affected individuals. Proximal lower limb weakness with onset in the first decade of life was noted in three individuals. Persistent elevations of serum creatine kinase (CK) levels were detected in 11 of 12 affected individuals, 1 of whom had an episode of rhabdomyolysis at 20years of age. Autism spectrum disorder or learning disabilities were reported in four individuals with the c.1567_1587 deletion. Muscle biopsies in eight affected individuals showed mixed myopathic and dystrophic findings, characterized by fiber size variability, internalized nuclei, and slightly increased extracellular connective tissue and inflammation. Immunofluorescence analysis of biopsies from five affected individuals showed reduced α-dystrobrevin immunoreactivity and variably reduced immunoreactivity of other DGC proteins: dystrophin, α, β, δ and γ-sarcoglycans, and α and β-dystroglycans. The DTNA deletion disrupted an interaction between α-dystrobrevin and syntrophin. Specific variants in the coiled-coil domain of DTNA cause skeletal muscle disease with variable penetrance. Affected individuals show a spectrum of clinical manifestations, with severity ranging from hyperCKemia, myalgias, and exercise intolerance to childhood-onset proximal muscle weakness. Our findings expand the molecular etiologies of both muscular dystrophy and paucisymptomatic hyperCKemia, to now include monoallelic DTNA variants as a novel cause of skeletal muscle disease in humans.

Uncovering the prominent role of satellite cells in paravertebral muscle development and aging by single-nucleus RNA sequencing

To uncover the role of satellite cells (SCs) in paravertebral muscle development and aging, we constructed a single-nucleus transcriptomic atlas of mouse paravertebral muscle across seven timepoints spanning the embryo (day 16.5) to old (month 24) stages. Eight cell types, including SCs, fast muscle cells, and slow muscle cells, were identified. An energy metabolism-related gene set, TCA CYCLE IN SENESCENCE, was enriched in SCs. Forty-two skeletal muscle disease-related genes were highly expressed in SCs and exhibited similar expression patterns. Among them, Pdha1 was the core gene in the TCA CYCLE IN SENESCENCE; Pgam2, Sod1, and Suclg1 are transcription factors closely associated with skeletal muscle energy metabolism. Transcription factor enrichment analysis of the 42 genes revealed that Myod1 and Mef2a were also highly expressed in SCs, which regulated Pdha1 expression and were associated with skeletal muscle development. These findings hint that energy metabolism may be pivotal in SCs development and aging. Three ligand-receptor pairs of extracellular matrix (ECM)-receptor interactions, Lamc1-Dag1, Lama2-Dag1, and Hspg2-Dag1, may play a vital role in SCs interactions with slow/fast muscle cells and SCs self-renewal. Finally, we built the first database of a skeletal muscle single-cell transcriptome, the Musculoskeletal Cell Atlas (http://www.mskca.tech), which lists 630,040 skeletal muscle cells and provides interactive visualization, a useful resource for revealing skeletal muscle cellular heterogeneity during development and aging. Our study could provide new targets and ideas for developing drugs to inhibit skeletal muscle aging and treat skeletal muscle diseases.

Reconstitution of depolarization-induced Ca2+ release for validation of skeletal muscle disease mutations and drug discovery.

In skeletal muscle, depolarization of the plasma membrane triggers Ca2+ release from the sarcoplasmic reticulum (SR),referred to as depolarization-induced Ca2+ release (DICR). DICR occurs via the type 1 ryanodine receptor (RyR1), which physically interacts with the dihydropyridine receptor Cav1.1 subunit in specific machinery formed with additional essential components including β1a, Stac3 adaptor protein and junctophilins. It has recently become clear that mutations in these components cause various skeletal muscle diseases. However, functional validation is time-consuming because it must be performed in a skeletal muscle environment and no specific treatment has been developed yet. In this study, we established a platform of the reconstituted DICR in HEK293 cells. The essential components were effectively transduced using baculovirus vectors, and Ca2+ release was quantitatively measured with R-CEPIA1er, a fluorescent ER Ca2+indicator. High [K+] depolarization triggered rapid Ca2+ release, indicating successful reconstitution of DICR. We evaluated several Cav1.1 mutations that are implicated in malignant hyperthermia and myopathy. We also tested several RyR1 inhibitors; whereas dantrolene and Cpd1 inhibited DICR, procaine had no effect. These results well reproduced the findings with the muscle fibers and the cultured myotubes. Since the procedure is simple and reproducible, the reconstituted DICR platform will be highly useful for validation of mutations and drug discovery for skeletal muscle diseases.

A molecular scale investigation of the mechanisms of contractile dysfunction for the hypertrophic cardiomyopathy MYH7 G256E mutation.

Genetic sequencing enables the pinpointing of specific genetic mutations correlated with striated muscle diseases. However, such associations do not describe mechanistic relationships between specific mutations and clinical phenotypes. To address this, we use CRISPR-edited human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) as a model system to probe how mutations in β-myosin heavy chain (MHC) lead to cardiac muscle disease. Preliminary data show that the specific force generation and activation rate of mutant G256E myofibrils is greater than isogenic control myofibrils. During relaxation, the initial, slow phase kinetics were decreased, indicating slower cross-bridge detachment rate. Additionally, stopped-flow mant-ATP assays on isolated myofibrils showed slower ATP binding for the G256E mutation, supporting delayed relaxation observed in myofibrils. Overall, these data suggest a hypercontractile phenotype with impaired early relaxation for the G256E mutation. To understand the molecular structure basis of these effects we have used molecular dynamics simulations of wild type and mutant β-MHC. In post-rigor (M.ATP) and rigor state simulations, we observed reduced stability in the transducer region of β-myosin, due to weakened hydrogen bonds between neighboring β-sheet strands as well as significant changes in local contacts. Pairing these in silico data with our in vitro data, our results suggest that the G256E mutation affects the transducer region of myosin such that it alters communication between the nucleotide binding pocket and the actin binding surface during the acto-myosin chemo-mechanical cycle, leading to hypercontractility and slowed relaxation.

Tangeretin alleviates Tunicamycin-induced endoplasmic reticulum stress and associated complications in skeletal muscle cells.

Endoplasmic reticulum (ER) stress and associated oxidative stress are involved in the genesis and progression of skeletal muscle diseases such as myositis and atrophy or muscle wasting. Targeting the ER stress and associated downstream pathways can aid in the development of better treatment strategies for these diseases with limited therapeutic approaches. There is a growing interest in identifying natural products against ER stress due to the lower toxicity and cost effectiveness. In the present study, we investigated the protective effect of Tangeretin, a citrus methoxyflavone found in citrus peels against Tunicamycin (pharmacological ER stress inducer)-induced ER stress and associated complications in rat skeletal muscle L6 cell lines. Treatment with Tunicamycin for a period of 24h resulted in the upregulation of ER stress marker proteins, ER resident oxidoreductases and cellular reactive oxygen species (ROS). Co-treatment with Tangeretin was effective in alleviating Tunicamycin-induced ER stress and associated redox-related complications by significantly downregulating the unfolded protein response (UPR), ER resident oxidoreductase proteins, cellular ROS and improving the antioxidant enzyme activity. Tunicamycin also induced upregulation of phosphorylated p38 MAP Kinase and loss of mitochondrial membrane potential. Tangeretin significantly reduced the levels of phosphorylated p38 MAP Kinase and improved the mitochondrial membrane potential. From the results, it is evident that Tangeretin can be explored further as a potential candidate for skeletal muscle diseases involving protein misfolding and ER stress.

Involutionary forms of skeletal muscle pathology

Involutionary forms of muscle pathology for the neurological community is ‘terra incognita’. The purpose of this publication is to describe clinical forms, pathogenesis, diagnostic and treatment methods of skeletal muscle diseases in the aging population.

Age-Related Dysfunction in Proteostasis and Cellular Quality Control in the Development of Sarcopenia

Sarcopenia is a debilitating skeletal muscle disease that accelerates in the last decades of life and is characterized by marked deficits in muscle strength, mass, quality, and metabolic health. The multifactorial causes of sarcopenia have proven difficult to treat and involve a complex interplay between environmental factors and intrinsic age-associated changes. It is generally accepted that sarcopenia results in a progressive loss of skeletal muscle function that exceeds the loss of mass, indicating that while loss of muscle mass is important, loss of muscle quality is the primary defect with advanced age. Furthermore, preclinical models have suggested that aged skeletal muscle exhibits defects in cellular quality control such as the degradation of damaged mitochondria. Recent evidence suggests that a dysregulation of proteostasis, an important regulator of cellular quality control, is a significant contributor to the aging-associated declines in muscle quality, function, and mass. Although skeletal muscle mammalian target of rapamycin complex 1 (mTORC1) plays a critical role in cellular control, including skeletal muscle hypertrophy, paradoxically, sustained activation of mTORC1 recapitulates several characteristics of sarcopenia. Pharmaceutical inhibition of mTORC1 as well as caloric restriction significantly improves muscle quality in aged animals, however, the mechanisms controlling cellular proteostasis are not fully known. This information is important for developing effective therapeutic strategies that mitigate or prevent sarcopenia and associated disability. This review identifies recent and historical understanding of the molecular mechanisms of proteostasis driving age-associated muscle loss and suggests potential therapeutic interventions to slow or prevent sarcopenia.