Programmed Cell Death and Senescence in Skeletal Muscle Stem Cells (original) (raw)

Molecular aging and rejuvenation of human muscle stem cells

EMBO Molecular Medicine, 2009

Very little remains known about the regulation of human organ stem cells (in general, and during the aging process), and most previous data were collected in short-lived rodents. We examined whether stem cell aging in rodents could be extrapolated to genetically and environmentally variable humans. Our findings establish key evolutionarily conserved mechanisms of human stem cell aging. We find that satellite cells are maintained in aged human skeletal muscle, but fail to activate in response to muscle attrition, due to diminished activation of Notch compounded by elevated transforming growth factor beta (TGF-b)/phospho Smad3 (pSmad3). Furthermore, this work reveals that mitogen-activated protein kinase (MAPK)/phosphate extracellular signal-regulated kinase (pERK) signalling declines in human muscle with age, and is important for activating Notch in human muscle stem cells. This molecular understanding, combined with data that human satellite cells remain intrinsically young, introduced novel therapeutic targets. Indeed, activation of MAPK/Notch restored 'youthful' myogenic responses to satellite cells from 70-year-old humans, rendering them similar to cells from 20-year-old humans. These findings strongly suggest that aging of human muscle maintenance and repair can be reversed by 'youthful' calibration of specific molecular pathways.

Muscle stem cell aging: identifying ways to induce tissue rejuvenation

Mechanisms of Ageing and Development, 2020

Aging is characterized by the functional and regenerative decline of tissues and organs. This regenerative decline is a consequence of the numerical and functional loss of adult stem cells, which are the corner stone of tissue homeostasis and repair. A palpable example of this decline is provided by skeletal muscle, a specialized tissue composed of postmitotic myofibers that contract to generate force. Skeletal muscle stem cells (satellite cells) are long-lived and support muscle regeneration throughout life, but at advanced age they fail for largely undefined reasons. Here, we discuss recent advances in the understanding of how satellite cells integrate diverse intrinsic and extrinsic processes to ensure optimal homeostatic function and how this integration is perturbed during aging, causing regenerative failure. With this increased understanding, it is now feasible to design and test interventions that delay satellite cell aging. We discuss the exciting new therapeutic potential of integrating and combining distinct anti-aging strategies for regenerative medicine.

A Population of Myogenic Stem Cells That Survives Skeletal Muscle Aging

Stem Cells, 2007

Age-related decline in integrity and function of differentiated adult tissues is widely attributed to reduction in number or regenerative potential of resident stem cells. The satellite cell, resident beneath the basal lamina of skeletal muscle myofibers, is the principal myogenic stem cell. Here we have explored the capacity of satellite cells within aged mouse muscle to regenerate skeletal muscle and to self-renew using isolated myofibers in tissue culture and in vivo. Satellite cells expressing Pax7 were depleted from aged muscles, and when aged myofibers were placed in culture, satellite cell myogenic progression resulted in apoptosis and fewer total differentiated progeny. However, a minority of cultured aged satellite cells generated large clusters of progeny containing both differentiated cells and new cells of a quiescent satellite-cell-like phenotype characteristic of self-renewal. Parallel in vivo engraftment assays showed that, despite the reduction in Pax7 ؉ cells, the satellite cell population associated with individual aged myofibers could regenerate muscle and self-renew as effectively as the larger population of satellite cells associated with young myofibers. We conclude that a minority of satellite cells is responsible for adult muscle regeneration, and that these stem cells survive the effects of aging to retain their intrinsic potential throughout life. Thus, the effectiveness of stem-cell-mediated muscle regeneration is determined by both extrinsic environmental influences and diversity in intrinsic potential of the stem cells themselves.

Molecular Regulation and Rejuvenation of Muscle Stem (Satellite) Cell Aging

The Indonesian Biomedical Journal, 2015

Age-related muscle loss leads to lack of muscle strength, resulting in reduced posture and mobility and an increased risk of falls, all of which contribute to a decrease in quality of life. Skeletal muscle regeneration is a complex process, which is not yet completely understood. CONTENT: Skeletal muscle undergoes a progressive agerelated loss in mass and function. Preservation of muscle mass depends in part on satellite cells, the resident stem cells of skeletal muscle. Reduced satellite cell function may contribute to the age-associated decrease in muscle mass. Recent studies have delineated that the aging process in organ stem cells is largely caused by age-speciic changes in the differentiated niches, and that regenerative outcomes often depend on the age of the niche, rather than on stem cell age. It is likely that epigenetic states will be better deine such key satellite cell features as prolonged quiescence and lineage idelity. It is also likely that DNA and histone modiications will underlie many of the changes in aged satellite cells that account for age-related declines in functionality and rejuvenation through exposure to the systemic environment. SUMMARY: Skeletal muscle aging results in a gradual loss of skeletal muscle mass, skeletal muscle function and regenerative capacity, which can lead to sarcopenia and increased mortality. Although the mechanisms underlying sarcopenia remain unclear, the skeletal muscle stem cell, or satellite cell, is required for muscle regeneration. Decreased muscle stem cell function in aging has long been shown to depend on altered environmental cues, whereas the contribution of intrinsic mechanisms remained less clear. Signals in the aged niche were shown to cause permanent defects in the ability of satellite cells to return to quiescence, ultimately also impairing the maintenance of self-renewing satellite cells. Therefore, only anti-aging strategies taking both factors, the stem cell niche and the stem cells per se, into consideration may ultimately be successful.

Faculty of 1000 evaluation for The aged niche disrupts muscle stem cell quiescence

F1000 - Post-publication peer review of the biomedical literature, 2000

The niche is a conserved regulator of stem cell quiescence and function. During aging, stem cell function declines. To what extent and by which means age-related changes within the niche contribute to this phenomenon are unknown. We demonstrate that the aged muscle stem cell niche, the muscle fiber, expresses FGF2 under homeostatic conditions, driving a subset of satellite cells to break quiescence and lose self-renewing capacity. We show that relatively dormant aged satellite cells robustly express Sprouty1 (spry1), an inhibitor of FGF signalling. Increasing FGF signalling in aged satellite cells under homeostatic conditions by removing spry1, results in the loss of quiescence, satellite cell depletion and diminished regenerative capacity. Conversely, reducing niche-derived FGF activity through inhibition of FGFR1 signalling or overexpression of spry1 in satellite cells prevents their depletion. These experiments identify an age-dependent change in the stem cell niche that directly influences stem cell quiescence and function. AUTHOR CONTRIBUTION JVC designed and performed experiments, analysed data, interpreted results and wrote the manuscript. KMJ performed experiments, analysed data and edited the manuscript. MAB conceived the project, designed experiments and interpreted results, and edited the manuscript. ASB conceived the project, designed and interpreted experiments, and wrote the manuscript. The authors declare no competing financial interests.

The mitotic clock in skeletal muscle regeneration, disease and cell mediated gene therapy

Acta Physiologica Scandinavica, 2005

The regenerative capacity of skeletal muscle will depend on the number of available satellite cells and their proliferative capacity. We have measured both parameters in ageing, and have shown that although the proliferative capacity of satellite cells is decreasing during muscle growth, it then stabilizes in the adult, whereas the number of satellite cells decreases during ageing. We have also developed a model to evaluate the regenerative capacity of human satellite cells by implantation into regenerating muscles of immunodeficient mice. Using telomere measurements, we have shown that the proliferative capacity of satellite cells is dramatically decreased in muscle dystrophies, thus hampering the possibilities of autologous cell therapy. Immortalization by telomerase was unsuccessful, and we currently investigate the factors involved in cell cycle exits in human myoblasts. We have also observed that insulin-like growth factor-1 (IGF-1), a factor known to provoke hypertrophy, does not increase the proliferative potential of satellite cells, which suggests that hypertrophy is provoked by increasing the number of satellite cells engaged in differentiation, thus possibly decreasing the compartment of reserve cells. We conclude that autologous cell therapy can be applied to specific targets when there is a source of satellite cells which is not yet exhausted. This is the case of Oculo-Pharyngeal Muscular Dystrophy (OPMD), a late onset muscular dystrophy, and we participate to a clinical trial using autologous satellite cells isolated from muscles spared by the disease.

Functional dysregulation of stem cells during aging: a focus on skeletal muscle stem cells

FEBS Journal, 2013

Aging of an organism is associated with the functional decline of tissues and organs, as well as a sharp decline in the regenerative capacity of stem cells. A prevailing view holds that the aging rate of an individual depends on the ratio of tissue attrition to tissue regeneration. Therefore, manipulations that favor the balance towards regeneration may prevent or delay aging. Skeletal muscle is a specialized tissue composed of postmitotic myofibers that contract to generate force. Satellite cells are the adult stem cells responsible for skeletal muscle regeneration. Recent studies on the biology of skeletal muscle and satellite cells in aging have uncovered the critical impact of systemic and niche factors on stem cell functionality and demonstrated the capacity of aged satellite cells to rejuvenate and increase their regenerative potential when exposed to a youthful environment. Here we review the current literature on the coordinated relationship between cell extrinsic and intrinsic factors that regulate the function of satellite cells, and ultimately determine tissue homeostasis and repair during aging, and which encourage the search for new anti-aging strategies.

Loss of heterogeneity, quiescence, and differentiation in muscle stem cells

Stem Cell Investigation, 2018

Satellite cell heterogeneity Muscle growth during embryogenesis, and muscle homeostasis and replacement upon injury in the adult rely on muscle stem cells, referred to as satellite cells. Satellite cells are quiescent and become activated following injury. Activation results in extensive cell proliferation (proliferating satellite cells are called myoblasts), followed by myogenic differentiation and fusion of differentiated cells into myotubes and then myofibers that repair the muscle. During myotube formation, a small fraction of satellite cells self-renews and returns to the quiescent state, thereby providing a reservoir for future muscle repair. A single muscle myofiber contains multiple nuclei (up to several hundred in mice), which result from fusion of differentiated myogenic cells and they are post-mitotic. Adult myogenesis involves all phases of the cell cycle, and also a reversible (satellite cells) and irreversible (post-mitotic myogenic cells) cell cycle exit (Figure 1). In the embryo, where stem cells continually yield differentiating cells to ensure tissue genesis, muscle stem cells proliferate and they enter quiescence during the perinatal period in the mouse (1), therefore, these cells essentially explore cell cycle progression. Muscle stem cells are defined by transcriptional programs that rely on both Pax3 and Pax7 transcription factors, the Mini-Review

Human muscle stem cells are refractory to aging

Aging Cell, 2021

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.