Rejuvenation of the muscle stem cell population restores strength to injured aged muscles (original) (raw)
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F1000 - Post-publication peer review of the biomedical literature, 2014
The aged suffer from progressive muscle weakness and regenerative failure. We demonstrate that muscle regeneration is impaired with aging due in part to a cell-autonomous functional decline in skeletal muscle stem cells (MuSCs). Two-thirds of aged MuSCs are intrinsically defective relative to young MuSCs, with reduced capacity to repair myofibers and repopulate the stem cell reservoir in vivo following transplantation due to a higher incidence of cells that express senescence markers and that have elevated p38α/β MAPK activity. We show that these limitations cannot be overcome by transplantation into the microenvironment of young recipient muscles. In contrast, subjecting the aged MuSC population to transient inhibition of p38α/β in conjunction with culture on soft hydrogel substrates rapidly expands the residual functional aged MuSC population, rejuvenating its potential for regeneration, serial transplantation, and strengthening damaged muscles of aged mice. These findings reveal a synergy between biophysical and biochemical cues that provides a paradigm for a localized autologous muscle stem cell therapy in aged individuals. Users may view, print, copy, download and text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
The central role of muscle stem cells in regenerative failure with aging
Nature medicine, 2015
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 unde...
Rejuvenating stem cells to restore muscle regeneration in aging
F1000Research, 2017
Adult muscle stem cells, originally called satellite cells, are essential for muscle repair and regeneration throughout life. Besides a gradual loss of mass and function, muscle aging is characterized by a decline in the repair capacity, which blunts muscle recovery after injury in elderly individuals. A major effort has been dedicated in recent years to deciphering the causes of satellite cell dysfunction in aging animals, with the ultimate goal of rejuvenating old satellite cells and improving muscle function in elderly people. This review focuses on the recently identified network of cell-intrinsic and -extrinsic factors and processes contributing to the decline of satellite cells in old animals. Some studies suggest that aging-related satellite-cell decay is mostly caused by age-associated extrinsic environmental changes that could be reversed by a "youthful environment". Others propose a central role for cell-intrinsic mechanisms, some of which are not reversed by env...
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.
Skeletal muscle aging results in a gradual loss of skeletal muscle mass, skeletal muscle function and decreased regenerative capacity, which can lead to sarcopenia and increased mortality. While the mechanisms underlying sarcopenia remain unclear, the skeletal muscle stem cell, or satellite cell, is required for muscle regeneration. Therefore, identification of signaling pathways affecting satellite cell function during aging may provide insights into therapeutic targets for combating sarcopenia. Here, we show that a cell-autonomous loss in self-renewal occurs via alterations in FGF Receptor 1 and p38αβ MAPK signaling in aged satellite cells. We further demonstrate that pharmacological manipulation of these pathways can ameliorate age-associated self-renewal defects. Thus, our data highlight an age-associated deregulation of a satellite cell homeostatic network and reveal potential therapeutic opportunities for the treatment of progressive muscle wasting.
Impact of ageing on muscle cell regeneration
Ageing research reviews, 2011
Skeletal muscle regeneration is a coordinate process in which several factors are sequentially activated to maintain and preserve muscle structure and function. The major role in the growth, remodeling and regeneration is played by satellite cells, a quiescent population of myogenic cells that reside between the basal lamina and plasmalemma and are rapidly activated in response to appropriate stimuli. However, in several muscle conditions, including aging, the capacity of skeletal muscle to sustain an efficient regenerative pathway is severely compromised. Nevertheless, if skeletal muscle possesses a stem cell compartment it is not clear why the muscle fails to regenerate under pathological conditions. Either the resident muscle stem cells are too rare or intrinsically incapable of repairing major damage, or perhaps the injured/pathological muscle is a prohibitive environment for stem cell activation and function. Although we lack definitive answers, recent experimental evidences su...
Human muscle stem cells are refractory to aging
Aging Cell, 2021
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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.
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.
Reduced growth rate of aged muscle stem cells is associated with impaired mechanosensitivity
Aging, 2022
Aging-associated reduction in muscle regeneration after injury and loss of muscle mass is referred to as sarcopenia [1, 2]. Prime mechanistic factors underlying the loss of muscle mass are myofiber atrophy and loss of myofibers [2]. This myofiber loss is attributed to an impaired regenerative capacity of aged muscle and associated muscle stem cells (MuSCs) [3]. Muscle regeneration relies on the proper functioning of myofibers and their associated MuSCs, which are selfrenewing skeletal muscle precursor cells involved in www.aging-us.com