Mechanisms of Muscle Injury, Repair, and Regeneration
TL;DR: The process of muscle injury, repair and regeneration that occurs in muscular dystrophy is used as an example of chronic muscle injury to highlight similarities and differences between the injury and repair processes that occur in acutely and chronically injured muscle.
Abstract: Skeletal muscle continuously adapts to changes in its mechanical environment through modifications in gene expression and protein stability that affect its physiological function and mass. However, mechanical stresses commonly exceed the parameters that induce adaptations, producing instead acute injury. Furthermore, the relatively superficial location of many muscles in the body leaves them further vulnerable to acute injuries by exposure to extreme temperatures, contusions, lacerations or toxins. In this article, the molecular, cellular, and mechanical factors that underlie muscle injury and the capacity of muscle to repair and regenerate are presented. Evidence shows that muscle injuries that are caused by eccentric contractions result from direct mechanical damage to myofibrils. However, muscle pathology following other acute injuries is largely attributable to damage to the muscle cell membrane. Many feaures in the injury-repair-regeneration cascade relate to the unregulated influx of calcium through membrane lesions, including: (i) activation of proteases and hydrolases that contribute muscle damage, (ii) activation of enzymes that drive the production of mitogens and motogens for muscle and immune cells involved in injury and repair, and (iii) enabling protein-protein interactions that promote membrane repair. Evidence is also presented to show that the myogenic program that is activated by acute muscle injury and the inflammatory process that follows are highly coordinated, with myeloid cells playing a central role in modulating repair and regeneration. The early-invading, proinflammatory M1 macrophages remove debris caused by injury and express Th1 cytokines that play key roles in regulating the proliferation, migration, and differentiation of satellite cells. The subsequent invasion by anti-inflammatory, M2 macrophages promotes tissue repair and attenuates inflammation. Although this system provides an effective mechanism for muscle repair and regeneration following acute injury, it is dysregulated in chronic injuries. In this article, the process of muscle injury, repair and regeneration that occurs in muscular dystrophy is used as an example of chronic muscle injury, to highlight similarities and differences between the injury and repair processes that occur in acutely and chronically injured muscle.
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TL;DR: A more comprehensive understanding of the interplay of stem cell–intrinsic and extrinsic factors will set the stage for improving cell therapies capable of restoring tissue homeostasis and enhancing muscle repair in the aged.
Abstract: Skeletal muscle mass, function, and repair capacity all progressively decline with aging, restricting mobility, voluntary function, and quality of life. Skeletal muscle repair is facilitated by a population of dedicated muscle stem cells (MuSCs), also known as satellite cells, that reside in anatomically defined niches within muscle tissues. In adult tissues, MuSCs are retained in a quiescent state until they are primed to regenerate damaged muscle through cycles of self-renewal divisions. With aging, muscle tissue homeostasis is progressively disrupted and the ability of MuSCs to repair injured muscle markedly declines. Until recently, this decline has been largely attributed to extrinsic age-related alterations in the microenvironment to which MuSCs are exposed. However, as highlighted in this Perspective, recent reports show that MuSCs also progressively undergo cell-intrinsic alterations that profoundly affect stem cell regenerative function with aging. A more comprehensive understanding of the interplay of stem cell-intrinsic and extrinsic factors will set the stage for improving cell therapies capable of restoring tissue homeostasis and enhancing muscle repair in the aged.
316 citations
TL;DR: In a fraction of patients, an autoimmune myopathy may develop, characterized by the development of autoantibodies to the target enzyme, HMG-CoA reductase, which is associated with death from cardiovascular causes.
Abstract: Statins are widely used and lower the risk of death from cardiovascular causes. In a fraction of patients, an autoimmune myopathy may develop, characterized by the development of autoantibodies to the target enzyme, HMG-CoA reductase.
256 citations
TL;DR: Evidence is brought together that age- related changes in body fat distribution and metabolism might be key factors of a vicious cycle that can accelerate the ageing process and onset of age-related diseases.
Abstract: Obesity has become a major public health problem. Given the current increase in life expectancy, the prevalence of obesity also raises steadily among older age groups. The increase in life expectancy is often accompanied with additional years of susceptibility to chronic ill health associated with obesity in the elderly. Both obesity and ageing are conditions leading to serious health problems and increased risk for disease and death. Ageing is associated with an increase in abdominal obesity, a major contributor to insulin resistance and the metabolic syndrome. Obesity in the elderly is thus a serious concern and comprehension of the key mechanisms of ageing and age-related diseases has become a necessary matter. Here, we aimed to identify similarities underlying mechanisms related to both obesity and ageing. We bring together evidence that age-related changes in body fat distribution and metabolism might be key factors of a vicious cycle that can accelerate the ageing process and onset of age-related diseases.
241 citations
Cites background from "Mechanisms of Muscle Injury, Repair..."
...Studies on rodents showed that muscle mass repair mechanisms, such as activation of a quiescent population of myogenic cells, is dysfunctional in older individuals (Kalyani et al. 2014; Tidball 2011)....
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TL;DR: The impact of environmental stressors in contributing to muscle pathophysiology including atrophy, hypertrophy, and fibrosis is emphasized.
Abstract: Decades of research in skeletal muscle physiology have provided multiscale insights into the structural and functional complexity of this important anatomical tissue, designed to accomplish the task of generating contraction, force and movement. Skeletal muscle can be viewed as a biomechanical device with various interacting components including the autonomic nerves for impulse transmission, vasculature for efficient oxygenation, and embedded regulatory and metabolic machinery for maintaining cellular homeostasis. The "omics" revolution has propelled a new era in muscle research, allowing us to discern minute details of molecular cross-talk required for effective coordination between the myriad interacting components for efficient muscle function. The objective of this review is to provide a systems-level, comprehensive mapping the molecular mechanisms underlying skeletal muscle structure and function, in health and disease. We begin this review with a focus on molecular mechanisms underlying muscle tissue development (myogenesis), with an emphasis on satellite cells and muscle regeneration. We next review the molecular structure and mechanisms underlying the many structural components of the muscle: neuromuscular junction, sarcomere, cytoskeleton, extracellular matrix, and vasculature surrounding muscle. We highlight aberrant molecular mechanisms and their possible clinical or pathophysiological relevance. We particularly emphasize the impact of environmental stressors (inflammation and oxidative stress) in contributing to muscle pathophysiology including atrophy, hypertrophy, and fibrosis. This article is categorized under: Physiology > Mammalian Physiology in Health and Disease Developmental Biology > Developmental Processes in Health and Disease Models of Systems Properties and Processes > Cellular Models.
225 citations
Cites background from "Mechanisms of Muscle Injury, Repair..."
...Neutrophils represent the most abundant immune cells recruited to the site of injury (within the first 24 hr) with numbers declining past 24 hr, with increasing recruitment of macrophages by 48 hr after injury (Tidball, 2011)....
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TL;DR: The results demonstrate an enhanced myogenic differentiation with the formation of parallel aligned long-range myotubes within the 3D bioprinted fibers, further revealing maturation, sarcomerogenesis, and functionality.
223 citations
Cites background from "Mechanisms of Muscle Injury, Repair..."
...However, skeletal muscle cannot restore significant tissue loss that can arise after 10 severe trauma, invasive surgeries, or degenerative diseases [2,3]....
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References
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TL;DR: The evidence in favour of alternative macrophage activation by the TH2-type cytokines interleukin-4 (IL-4) and IL-13 is assessed, and its limits and relevance to a range of immune and inflammatory conditions are defined.
Abstract: The classical pathway of interferon-gamma-dependent activation of macrophages by T helper 1 (T(H)1)-type responses is a well-established feature of cellular immunity to infection with intracellular pathogens, such as Mycobacterium tuberculosis and HIV. The concept of an alternative pathway of macrophage activation by the T(H)2-type cytokines interleukin-4 (IL-4) and IL-13 has gained credence in the past decade, to account for a distinctive macrophage phenotype that is consistent with a different role in humoral immunity and repair. In this review, I assess the evidence in favour of alternative macrophage activation in the light of macrophage heterogeneity, and define its limits and relevance to a range of immune and inflammatory conditions.
5,930 citations
TL;DR: Recent evidence suggests that differential modulation of the chemokine system integrates polarized macrophages in pathways of resistance to, or promotion of, microbial pathogens and tumors, or immunoregulation, tissue repair and remodeling.
5,568 citations
TL;DR: Recent studies have shown that monocyte heterogeneity is conserved in humans and mice, allowing dissection of its functional relevance: the different monocyte subsets seem to reflect developmental stages with distinct physiological roles, such as recruitment to inflammatory lesions or entry to normal tissues.
Abstract: Heterogeneity of the macrophage lineage has long been recognized and, in part, is a result of the specialization of tissue macrophages in particular microenvironments. Circulating monocytes give rise to mature macrophages and are also heterogeneous themselves, although the physiological relevance of this is not completely understood. However, as we discuss here, recent studies have shown that monocyte heterogeneity is conserved in humans and mice, allowing dissection of its functional relevance: the different monocyte subsets seem to reflect developmental stages with distinct physiological roles, such as recruitment to inflammatory lesions or entry to normal tissues. These advances in our understanding have implications for the development of therapeutic strategies that are targeted to modify particular subpopulations of monocytes.
4,861 citations
TL;DR: The identification of the mdx mouse as an animal model for DMD has important implications with regard to the etiology of the lethal DMD phenotype, and the protein dystrophin is named because of its identification via the isolation of the Duchenne muscular dystrophy locus.
4,357 citations
TL;DR: In the course of an electron microscopic study of the peripheral region of the skeletal muscle fiber of the frog, the presence of certain cells, intimately associated with the muscle fiber, have been observed which the authors have chosen to call satellite cells.
Abstract: In the course of an electron microscopic study of the peripheral region of the skeletal muscle fiber of the frog, the presence of certain cells, intimately associated with the muscle fiber, have been observed which we have chosen to call satellite cells. Since these cells have not been reported previously and indeed might be of interest to students of muscle histology and furthermore, as we shall suggest, might be pertinent to the vexing problem of skeletal muscle regeneration, a brief communication describing this finding is warranted prior to a more detailed study. The observations reported here have been made on bundles of fibers dissected from the tibialis anticus muscle of the frog. The material has been fixed by the conventional method with osmium tetroxide, and the embedding has been carried out with methacrylate and with epoxy (epon) resin. In sections that were \"stained,\" the lead hydroxide solution of Watson (1) was used. As seen in the attached electron micrograph of the satellite cell, the striking paucity of cytoplasm relative to its nucleus results in the cell assuming the shape of the nucleus. In fact, it is virtually impossible to discern the cellular nature of this entity in the light microscope, as it appears to be indistinguishable from a peripheral muscle nucleus proper. In electron micrographs the cell is seen \"wedged\" between the plasma membrane of the muscle fiber and the basement membrane, which invests the fiber throughout its length in close association with the plasma membrane. The intimacy of this satellite cell with respect to the multinucleate muscle cell is further revealed in the fact that, in general, the surface of the muscle fiber is not distorted outward but instead the satellite cell protrudes inward pushing the myofibrils of the muscle cell aside. On the inner surface, the plasma membrane of the satellite cell is in appositon with the plasma membrane of the muscle cell. Unfortunately, because of the limited observations and the difficulty in acquiring sufficient data readily with electron micrographic techniques, it is not possible at present to estimate the frequency of occurrence of these cells in a typical muscle fiber in our preparation of tibialis anticus muscle. The only generalization warranted at this time is that the peripheral muscle nuclei proper occur much more frequently than the satellite cells. It is interesting that upon alerting other investigators to these findings, similar cells have been found in electron micrographs of two other muscles of the frog, namely sartorius (2) and ileofibularis (3), and of the sartorius and tongue muscle of the white rat (4). (Though the direct evidence is restricted to these two vertebrates, it seems reasonable to hazard a guess that skeletal muscle fibers of vertebrates in general contain satellite cells.) It is tempting to speculate about the origin and the role of the satellite cells. Before stating the several possible hypotheses that have figured in our interpretations, it is pertinent to recall a most striking characteristic of regenerating muscle fibers in the least ambiguous case where the sarcolemma-tube remains intact, the myoplasm having undergone hyaline formation and retraction as a result of trauma. Within 48 hours a marked presence of \"free cells\" is noted in the empty tube, the cells appearing both as \"round\" and \" f u s i f o r m \" types (5). Moreover, in tissue culture studies of mature skeletal muscle explants, fi'ee cells are also seen emanating from the explant. The central question must be asked: what is the origin of these cells? Most cytologists lean toward the interpretation that surviving nuclei in the damaged multinucleate muscle cell give rise to single cells by \"gathering up\" cytoplasm from the sarcoplasm of the muscle cell--an unusual mechanism, however, for vertebrate systems. If this point of view is taken, the first and immediate hypothesis suggests itself, namely, that in the resting state some cells are being produced at a slow rate by the above mechanism and reside just outside the plasma membrane of the muscle cell, and that upon being stimulated by trauma, e.g. ischemia, mechanical compression, toxic agents, etc., the rate of production of such cells is increased. The second hypothesis, more in keeping with conventional notions of cytology, is that the satellite cells are remnants from the embryonic development of the multinucleate muscle cell which results from the process of fusion of individual myoblasts. Thus the satellite cells are
3,364 citations