The molecular basis of skeletal muscle atrophy (original) (raw)
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Cellular and molecular mechanisms of muscle atrophy
Disease Models & Mechanisms, 2012
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 mus...
Regulation of skeletal muscle atrophy
The Journal of Physical Fitness and Sports Medicine, 2013
Skeletal muscle atrophy can result from prolonged periods of skeletal muscle inactivity due to bed rest, denervation, or unloading. Such unloading-associated atrophy of skeletal muscle is characterized by both an increase in protein degradation and a decrease in protein synthesis. Successful treatments for skeletal muscle atrophy could either block protein degradation pathways activated during atrophy, or stimulate protein synthesis pathways induced during skeletal muscle hypertrophy. In this review, we mainly focus on the Insulin-like growth factor 1 (IGF-1)/Insulin receptor substrate 1 (IRS-1) pathway in muscle, because there is increasing evidence indicating that inhibition of this pathway in muscle is involved in the progression of disuse atrophy. We also focus on the signaling pathways that control skeletal muscle atrophy, including muscle atrophy-associated ubiqitin ligases such as Cbl-b, muscle RING finger 1 (MuRF1), and muscle atrophy F-box (MAFbx)/atrogin-1.
Introduction to the Special Issue “Skeletal Muscle Atrophy: Mechanisms at a Cellular Level”
Cells
Skeletal muscle is the most abundant tissue in the body and requires high levels of energy to function properly. Skeletal muscle allows voluntary movement and body posture, which require different types of fiber, innervation, energy, and metabolism. Here, we summarize the contribution received at the time of publication of this Introductory Issue for the Special Issue dedicated to “Skeletal Muscle Atrophy: Mechanisms at a Cellular Level”. The Special Issue is divided into three sections. The first is dedicated to skeletal muscle pathophysiology, the second to disease mechanisms, and the third to therapeutic development.
American Journal of Physiology-Cell Physiology
Decreased skeletal muscle contractile activity (disuse) or unloading leads to muscle mass loss, also known as muscle atrophy. The balance between muscle protein synthesis (MPS) and muscle protein breakdown (MPB) is the primary determinant of skeletal muscle mass. A reduced mechanical load on skeletal muscle is one of the main external factors leading to muscle atrophy. However, endocrine and inflammatory factors can act synergistically in catabolic states, amplifying the atrophy process and accelerating its progression. In addition, older individuals display aging-induced anabolic resistance, which can predispose this population to more pronounced effects when exposed to periods of reduced physical activity or mechanical unloading. Different cellular mechanisms contribute to the regulation of muscle protein balance during skeletal muscle atrophy. This review summarizes the effects of muscle disuse on muscle protein balance and the molecular mechanisms involved in muscle atrophy in t...
Biochemical Journal, 1995
The rapid loss of skeletal-muscle protein during starvation and after denervation occurs primarily through increased rates of protein breakdown and activation of a non-lysosomal ATP-dependent proteolytic process. To investigate whether protein flux through the ubiquitin (Ub)-proteasome pathway is enhanced, as was suggested by related studies, we measured, using specific polyclonal antibodies, the levels of Ub-conjugated proteins in normal and atrophying muscles. The content of these critical intermediates had increased 50-250% after food deprivation in the extensor digitorum longus and soleus muscles 2 days after denervation. Like rates of proteolysis, the amount of Ub-protein conjugates and the fraction of Ub conjugated to proteins increased progressively during food deprivation and returned to normal within 1 day of refeeding. During starvation, muscles of adrenalectomized rats failed to increase protein breakdown, and they showed 50% lower levels of Ub-protein conjugates than tho...
Mechanisms of muscle atrophy and hypertrophy: implications in health and disease
Nature Communications, 2021
Skeletal muscle is the protein reservoir of our body and an important regulator of glucose and lipid homeostasis. Consequently, the growth or the loss of muscle mass can influence general metabolism, locomotion, eating and respiration. Therefore, it is not surprising that excessive muscle loss is a bad prognostic index of a variety of diseases ranging from cancer, organ failure, infections and unhealthy ageing. Muscle function is influenced by different quality systems that regulate the function of contractile proteins and organelles. These systems are controlled by transcriptional dependent programs that adapt muscle cells to environmental and nutritional clues. Mechanical, oxidative, nutritional and energy stresses, as well as growth factors or cytokines modulate signaling pathways that, ultimately, converge on protein and organelle turnover. Novel insights that control and orchestrate such complex network are continuously emerging and will be summarized in this review. Understanding the mechanisms that control muscle mass will provide therapeutic targets for the treatment of muscle loss in inherited and non hereditary diseases and for the improvement of the quality of life during ageing.
American journal of physiology. Endocrinology and metabolism, 2016
Muscle wasting resulting wholly or in part from disuse represents a serious medical complication, which when prolonged, can increase morbidity and mortality. Although much knowledge has been gained over the past half century, the underlying etiology by which disuse alters muscle proteostasis remains enigmatic. Multidisciplinary and novel methodologies are needed to fill gaps and overcome barriers to improved patient care. The present review highlights seminal concepts from a symposium at Experimental Biology 2016. These proceedings focus on the: (1) role of insulin resistance in mediating disuse-induced changes in muscle protein synthesis (MPS) and breakdown (MPB), as well as cross-talk between carbohydrate and protein metabolism; (2) the relative importance of MPS/MPB in mediating involuntary muscle loss in humans and animals; (3) interpretative limitations associated with MPS/MPB "markers" e.g. MuRF1/MAFbx mRNA; and finally, (4) how OMIC technologies can be leveraged to ...
Regulation of ATP-ubiquitin-dependent proteolysis in muscle wasting
Reproduction Nutrition Development, 1994
― Protein breakdown plays a major role in muscle growth and atrophy. However, the regulation of muscle proteolysis by nutritional, hormonal and mechanical factors remains poorly understood. In this review, the methods available to study skeletal muscle protein breakdown, and our current understanding of the role of 3 major proteolytic systems that are well characterized in this tissue (ie the lysosomal, Ca 2 +-dependent and ATP-ubiquitin-dependent proteolytic pathways) are critically analyzed. ATP-ubiquitin-dependent proteolysis is discussed in particular since recent data strongly suggest that this pathway may be responsible for the loss of myofibrillar proteins in many muscle-wasting conditions in rodents. In striking contrast to either the lysosomal or the Ca 2 +-dependent processes, ATP-ubiquitin-dependent protein breakdown is systematically influenced by nutritional manipulation (fasting and dietary protein deficiency), muscle activity and disuse (denervation atrophy and simulated weightlessness), as well as pathological conditions (sepsis, cancer, trauma and acidosis). The hormonal control of this pathway, its possible substrates, rate-limiting step, and functional associations with other proteolytic systems are discussed. skeletal muscle / protein breakdown / ubiquitin / proteasome Résumé ― Régulation de la protéolyse musculaire ATP-ubiquitine-dépendante au cours des états cataboliques. La protéolyse joue un rôle majeur dans le contrôle de la croissance ou de l'atrophie musculaire. Cependant, ses mécanismes de régulation par les nutriments, les facteurs hormonaux ou l'activité musculaire sont encore peu connus. Cette revue analyse de façon critique les différentes techniques disponibles pour étudier la dégradation des protéines musculaires, et le rôle des 3 systèmes protéolytiques majeurs bien caractérisés dans ce tissu, c'est-à-dire la voie lysosomaie, Ca 2 +-dépendante et A TP-ubiquitine-dépendante. La protéolyse A 7'P-uo;qu;f<ne-dépendanfe est plus particulièrement évoquée, car des travaux récents suggèrent que cette voie serait responsable de la dégradation des protéines contractiles majeures au cours de multiples états cataboliques chez les rongeurs. Contrairement aux systèmes protéolytiques lysosomal et Ca 2 ·-dépendant, la protéolyse ATP-ubiquitinedépendante est systématiquement influencée par les manipulations nutritionnelles (jeûne, régime déficient en protéines), l'activité et l'inactivité musculaire (dénervation, apesanteur simulée), et de nombreux états pathologiques (infections, cancers, traumatismes, acidose). La régulation hormonale, les substrats possibles, l'étape limitante et la coordination fonctionnelle de cette voie de la protéolyse avec les autres systèmes protéolytiques sont discutés. muscle squelettique / protéolyse / ubiquitine lprotéasome
Patterns of gene expression in atrophying skeletal muscles: response to food deprivation
Faseb Journal, 2002
During fasting and many systemic diseases, muscle undergoes rapid loss of protein and functional capacity. To define the transcriptional changes triggering muscle atrophy and energy conservation in fasting, we used cDNA microarrays to compare mRNAs from muscles of control and food-deprived mice. Expression of >94% of genes did not change, but interesting patterns emerged among genes that were differentially expressed: 1) mRNAs encoding polyubiquitin, ubiquitin extension proteins, and many (but not all) proteasome subunits increased, which presumably contributes to accelerated protein breakdown; 2) a dramatic increase in mRNA for the ubiquitin ligase, atrogin-1, but not most E3s; 3) a significant suppression of mRNA for myosin binding protein H (but not other myofibrillar proteins) and IGF binding protein 5, which may favor cell protein loss; 4) decreases in mRNAs for several glycolytic enzymes and phosphorylase kinase subunits, and dramatic increases in mRNAs for pyruvate dehydrogenase kinase 4 and glutamine synthase, which should promote glucose sparing and gluconeogenesis. During fasting, metallothionein mRNA increased dramatically, mRNAs for extracellular matrix components fell, and mRNAs that may favor cap-independent mRNA translation rose. Significant changes occurred in mRNAs for many growth-related proteins and transcriptional regulators. These transcriptional changes indicate a complex adaptive program that should favor protein degradation and suppress glucose oxidation in muscle. Similar analysis of muscles atrophying for other causes is allowing us to identify a set of atrophy-specific changes in gene expression.-Jagoe, R. T., Lecker, S. H., Gomes, M., Goldberg, A. L. Patterns of gene expression in atrophying skeletal muscles: response to food deprivation.
Atrophy responses to muscle inactivity. I. Cellular markers of protein deficits
Journal of Applied Physiology, 2003
The goal of this study was to use the model of spinal cord isolation (SI), which blocks nearly all neuromuscular activity while leaving the motoneuron muscle-fiber connections intact, to characterize the cellular processes linked to marked muscle atrophy. Rats randomly assigned to normal control and SI groups were studied at 0, 2, 4, 8, and 15 days after SI surgery. The slow soleus muscle atrophied by ∼50%, with the greatest degree of loss occurring during the first 8 days. Throughout the SI duration, muscle protein concentration was maintained at the control level, whereas myofibrillar protein concentration steadily decreased between 4 and 15 days of SI, and this was associated with a 50% decrease in myosin heavy chain (MHC) normalized to total protein. Actin relative to the total protein was maintained at the control level. Marked reductions occurred in total RNA and DNA content and in total MHC and actin mRNA expressed relative to 18S ribosomal RNA. These findings suggest that tw...