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Muscle stem cells (MuSCs) are specialized cells that reside in adult skeletal muscle poised to repair muscle tissue. The ability of MuSCs to regenerate damaged tissues declines markedly with aging and in diseases such as Duchenne muscular dystrophy, but the underlying causes of MuSC dysfunction remain poorly understood. Both aging and disease result in dramatic increases in the stiffness of the muscle tissue microenvironment from fibrosis. MuSCs are known to lose their regenerative potential if cultured on stiff plastic substrates. We sought to determine whether MuSCs harbor a memory of their past microenvironment and if it can be overcome. We tested MuSCs in situ using dynamic hydrogel biomaterials that soften or stiffen on demand in response to light and found that freshly isolated MuSCs develop a persistent memory of substrate stiffness characterized by loss of proliferative progenitors within the first three days of culture on stiff substrates. MuSCs cultured on soft hydrogels had altered cytoskeletal organization and activity of Rho and Rac guanosine triphosphate hydrolase (GTPase) and Yes-associated protein mechanotransduction pathways compared to those on stiff hydrogels. Pharmacologic inhibition identified RhoA activation as responsible for the mechanical memory phenotype, and single-cell RNA sequencing revealed a molecular signature of the mechanical memory. These studies highlight that microenvironmental stiffness regulates MuSC fate and leads to MuSC dysfunction that is not readily reversed by changing stiffness. Our results suggest that stiffness can be circumvented by targeting downstream signaling pathways to overcome stem cell dysfunction in aged and disease states with aberrant fibrotic tissue mechanics., Competing Interests: Competing interests statement:H.M.B. is a named inventor on patent applications held by Stanford University regarding prostaglandin signaling and muscle regeneration licensed to Epirium Bio. Y.X.W., C.A.H., and H.M.B. are named inventors on a patent application held by Stanford University for processing of multiplex microscopy images. H.M.B. is a cofounder of Myoforte Therapeutics, which was acquired by Epirium Bio, and receives consulting fees and has equity and stock options from Epirium Bio. C.M.M., S.S, X.S., F.J.B., G.W., and I.A.F. declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

During aging, the regenerative capacity of muscle stem cells (MuSCs) decreases, diminishing the ability of muscle to repair following injury. We found that the ability of MuSCs to regenerate is regulated by the primary cilium, a cellular protrusion that serves as a sensitive sensory organelle. Abolishing MuSC cilia inhibited MuSC proliferation in vitro and severely impaired injury-induced muscle regeneration in vivo. In aged muscle, a cell intrinsic defect in MuSC ciliation was associated with the decrease in regenerative capacity. Exogenous activation of Hedgehog signaling, known to be localized in the primary cilium, promoted MuSC expansion, both in vitro and in vivo. Delivery of the small molecule Smoothened agonist (SAG1.3) to muscles of aged mice restored regenerative capacity leading to increased strength post-injury. These findings provide fresh insights into the signaling dysfunction in aged MuSCs and identify the ciliary Hedgehog signaling pathway as a potential therapeutic target to counter the loss of muscle regenerative capacity which accompanies aging., (© 2022. The Author(s).)

The impact of glucose metabolism on muscle regeneration remains unresolved. We identify glucose metabolism as a crucial driver of histone acetylation and myogenic cell fate. We use single-cell mass cytometry (CyTOF) and flow cytometry to characterize the histone acetylation and metabolic states of quiescent, activated, and differentiating muscle stem cells (MuSCs). We find glucose is dispensable for mitochondrial respiration in proliferating MuSCs, so that glucose becomes available for maintaining high histone acetylation via acetyl-CoA. Conversely, quiescent and differentiating MuSCs increase glucose utilization for respiration and have consequently reduced acetylation. Pyruvate dehydrogenase (PDH) activity serves as a rheostat for histone acetylation and must be controlled for muscle regeneration. Increased PDH activity in proliferation increases histone acetylation and chromatin accessibility at genes that must be silenced for differentiation to proceed, and thus promotes self-renewal. These results highlight metabolism as a determinant of MuSC histone acetylation, fate, and function during muscle regeneration., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Skeletal muscles harbor quiescent muscle-specific stem cells (MuSCs) capable of tissue regeneration throughout life. Muscle injury precipitates a complex inflammatory response in which a multiplicity of cell types, cytokines, and growth factors participate. Here we show that Prostaglandin E2 (PGE2) is an inflammatory cytokine that directly targets MuSCs via the EP4 receptor, leading to MuSC expansion. An acute treatment with PGE2 suffices to robustly augment muscle regeneration by either endogenous or transplanted MuSCs. Loss of PGE2 signaling by specific genetic ablation of the EP4 receptor in MuSCs impairs regeneration, leading to decreased muscle force. Inhibition of PGE2 production through nonsteroidal anti-inflammatory drug (NSAID) administration just after injury similarly hinders regeneration and compromises muscle strength. Mechanistically, the PGE2 EP4 interaction causes MuSC expansion by triggering a cAMP/phosphoCREB pathway that activates the proliferation-inducing transcription factor, Nurr1 Our findings reveal that loss of PGE2 signaling to MuSCs during recovery from injury impedes muscle repair and strength. Through such gain- or loss-of-function experiments, we found that PGE2 signaling acts as a rheostat for muscle stem-cell function. Decreased PGE2 signaling due to NSAIDs or increased PGE2 due to exogenous delivery dictates MuSC function, which determines the outcome of regeneration. The markedly enhanced and accelerated repair of damaged muscles following intramuscular delivery of PGE2 suggests a previously unrecognized indication for this therapeutic agent., Competing Interests: Conflict of interest statement: A.T.V.H., A.R.P., and H.M.B. are named inventors on a patent related to the findings in this paper. H.M.B. and S.L.D. are cofounders of the company Myoforte.

Dystrophin is expressed in differentiated myofibers, in which it is required for sarcolemmal integrity, and loss-of-function mutations in the gene that encodes it result in Duchenne muscular dystrophy (DMD), a disease characterized by progressive and severe skeletal muscle degeneration. Here we found that dystrophin is also highly expressed in activated muscle stem cells (also known as satellite cells), in which it associates with the serine-threonine kinase Mark2 (also known as Par1b), an important regulator of cell polarity. In the absence of dystrophin, expression of Mark2 protein is downregulated, resulting in the inability to localize the cell polarity regulator Pard3 to the opposite side of the cell. Consequently, the number of asymmetric divisions is strikingly reduced in dystrophin-deficient satellite cells, which also display a loss of polarity, abnormal division patterns (including centrosome amplification), impaired mitotic spindle orientation and prolonged cell divisions. Altogether, these intrinsic defects strongly reduce the generation of myogenic progenitors that are needed for proper muscle regeneration. Therefore, we conclude that dystrophin has an essential role in the regulation of satellite cell polarity and asymmetric division. Our findings indicate that muscle wasting in DMD not only is caused by myofiber fragility, but also is exacerbated by impaired regeneration owing to intrinsic satellite cell dysfunction.

Muscle stem cells, termed satellite cells, are crucial for skeletal muscle growth and regeneration. In healthy adult muscle, satellite cells are quiescent but poised for activation. During muscle regeneration, activated satellite cells transiently re-enter the cell cycle to proliferate and subsequently exit the cell cycle to differentiate or self-renew. Recent studies have demonstrated that satellite cells are heterogeneous and that subpopulations of satellite stem cells are able to perform asymmetric divisions to generate myogenic progenitors or symmetric divisions to expand the satellite cell pool. Thus, a complex balance between extrinsic cues and intrinsic regulatory mechanisms is needed to tightly control satellite cell cycle progression and cell fate determination. Defects in satellite cell regulation or in their niche, as observed in degenerative conditions such as aging, can impair muscle regeneration. Here, we review recent discoveries of the intrinsic and extrinsic factors that regulate satellite cell behaviour in regenerating and degenerating muscles., (© 2015. Published by The Company of Biologists Ltd.)

Objective: To investigate the effect of chronic endurance exercise on microcirculatory reserve capacity of biceps brachii in Chinese rowers and provide a certain basis for the date standard foundation of monitoring of functional status and the foundation of database of reserve capacity of blood of Chinese rowers., Methods: Empty stomach in the morning, 77 rowers from different groups and 24 common health people were noninvasive tested by using PeriFlux System 5000, the test indexes include the microcirculatory reserve capacity and other related indexes of biceps brachii. The test sites of all athletes were the same space in biceps brachii of the right side of body, there was no space differences of all athletes . All athletes were tested in the relatively stable functional status, common people were healthy. The test value included basic values and heating values, put the before and after heating of microcirculatory blood perfusion (MBP) as the microcirculatory reserve capacity., Results: Heavyweight female (198. 97 ± 98. 81) > heavyweight male (183. 45 ± 64. 31) > lightweight male (151. 01 ± 65. 96) > lightweight female(140.53 ± 43.22) > common male people(127.21 ± 56.38) > common female people(103.54 ± 33.41), the microcirculatory reserve capacity of each group athletes were higher than common people, except the comparison between lightweight female and common male people, and there was no significant difference among the different group athletes., Conclusion: Chronic endurance exercise can improve the microcirculatory reserve capacity of rowers, especially the heavyweight rowers; the normal value of microcirculatory reserve capacity of heavy weight rowers should be more than 160, and lightweight rowers should be more than 120. There was no significant difference among different sex athletes, if the value of microcirculatory reserve capacity is significant lower than normal, it shows that athletes are in the state of fatigue.

Muscle stem cells facilitate the long-term regenerative capacity of skeletal muscle. This self-renewing population of satellite cells has only recently been defined through genetic and transplantation experiments. Although muscle stem cells remain in a dormant quiescent state in uninjured muscle, they are poised to activate and produce committed progeny. Unlike committed myogenic progenitor cells, the self-renewal capacity gives muscle stem cells the ability to engraft as satellite cells and capitulate long-term regeneration. Similar to other adult stem cells, understanding the molecular regulation of muscle stem cells has significant implications towards the development of pharmacological or cell-based therapies for muscle disorders. This Cell Science at a Glance article and accompanying poster will review satellite cell characteristics and therapeutic potential, and provide an overview of the muscle stem cell hallmarks: quiescence, self-renewal and commitment., (© 2014. Published by The Company of Biologists Ltd.)

Wnt7a/Fzd7 signaling stimulates skeletal muscle growth and repair by inducing the symmetric expansion of satellite stem cells through the planar cell polarity pathway and by activating the Akt/mTOR growth pathway in muscle fibers. Here we describe a third level of activity where Wnt7a/Fzd7 increases the polarity and directional migration of mouse satellite cells and human myogenic progenitors through activation of Dvl2 and the small GTPase Rac1. Importantly, these effects can be exploited to potentiate the outcome of myogenic cell transplantation into dystrophic muscles. We observed that a short Wnt7a treatment markedly stimulated tissue dispersal and engraftment, leading to significantly improved muscle function. Moreover, myofibers at distal sites that fused with Wnt7a-treated cells were hypertrophic, suggesting that the transplanted cells deliver activated Wnt7a/Fzd7 signaling complexes to recipient myofibers. Taken together, we describe a viable and effective ex vivo cell modulation process that profoundly enhances the efficacy of stem cell therapy for skeletal muscle.

Satellite cells, the quintessential skeletal muscle stem cells, reside in a specialized local environment whose anatomy changes dynamically during tissue regeneration. The plasticity of this niche is attributable to regulation by the stem cells themselves and to a multitude of functionally diverse cell types. In particular, immune cells, fibrogenic cells, vessel-associated cells and committed and differentiated cells of the myogenic lineage have emerged as important constituents of the satellite cell niche. Here, we discuss the cellular dynamics during muscle regeneration and how disease can lead to perturbation of these mechanisms. To define the role of cellular components in the muscle stem cell niche is imperative for the development of cell-based therapies, as well as to better understand the pathobiology of degenerative conditions of the skeletal musculature.

Cell-based therapies for degenerative diseases of the musculature remain on the verge of feasibility. Myogenic cells are relatively abundant, accessible, and typically harbor significant proliferative potential ex vivo. However, their use for therapeutic intervention is limited due to several critical aspects of their complex biology. Recent insights based on mouse models have advanced our understanding of the molecular mechanisms controlling the function of myogenic progenitors significantly. Moreover, the discovery of atypical myogenic cell types with the ability to cross the blood-muscle barrier has opened exciting new therapeutic avenues. In this paper, we outline the major problems that are currently associated with the manipulation of myogenic cells and discuss promising strategies to overcome these obstacles., (Copyright © 2013 WILEY Periodicals, Inc.)

The genesis of skeletal muscle during embryonic development and postnatal life serves as a paradigm for stem and progenitor cell maintenance, lineage specification, and terminal differentiation. An elaborate interplay of extrinsic and intrinsic regulatory mechanisms controls myogenesis at all stages of development. Many aspects of adult myogenesis resemble or reiterate embryonic morphogenetic episodes, and related signaling mechanisms control the genetic networks that determine cell fate during these processes. An integrative view of all aspects of myogenesis is imperative for a comprehensive understanding of muscle formation. This article provides a holistic overview of the different stages and modes of myogenesis with an emphasis on the underlying signals, molecular switches, and genetic networks.