Muscle Stem Cell Regenerative Capacity Research Articles

Myofiber Baf60c controls muscle regeneration by modulating Dkk3-mediated paracrine signaling.

Obesity and type 2 diabetes (T2D) are the leading causes of the progressive decline in muscle regeneration and fitness in adults. The muscle microenvironment is known to play a key role in controlling muscle stem cell regenerative capacity, yet the underlying mechanism remains elusive. Here, we found that Baf60c expression in skeletal muscle is significantly downregulated in obese and T2D mice and humans. Myofiber-specific ablation of Baf60c in mice impairs muscle regeneration and contraction, accompanied by a robust upregulation of Dkk3, a muscle-enriched secreted protein. Dkk3 inhibits muscle stem cell differentiation and attenuates muscle regeneration in vivo. Conversely, Dkk3 blockade by myofiber-specific Baf60c transgene promotes muscle regeneration and contraction. Baf60c interacts with Six4 to synergistically suppress myocyte Dkk3 expression. While muscle expression and circulation levels of Dkk3 are markedly elevated in obese mice and humans, Dkk3 knockdown improves muscle regeneration in obese mice. This work defines Baf60c in myofiber as a critical regulator of muscle regeneration through Dkk3-mediated paracrine signaling.

Sarcopenia in aging, obesity, and cancer.

Sarcopenia, defined as loss of muscle mass, strength and physical performance, is a hallmark of aging and is invariably associated with perturbation of amino acid metabolism, increased muscle protein catabolism relative to anabolism, and loss of muscle fibers. Sarcopenia may be associated with general loss of body mass, or it may also occur along with obesity [sarcopenic obesity (SO)]. Although sarcopenia is associated with multiple comorbidities in older adults, its effects may even be more severe in patients with malignant disease where it has been shown to contribute to poor surgical outcomes, increased chemotherapy toxicity associated with both cytotoxic and targeted agents, as well as adversely impacting survival. While development of sarcopenia is a common age-related phenomenon, the associated catabolic processes appear to be promoted by physical inactivity, inadequate nutrition, and systemic low-grade inflammation, as well as intrinsic muscle and molecular changes, including mitochondrial dysfunction and impaired muscle stem cell regenerative capacity. Increased physical activity and adequate protein intake can reduce incidence and severity of sarcopenia in cancer patients, but many older cancer patients do not meet physical activity and nutrition recommendations, and cancer treatment can make it more difficult to make favorable lifestyle changes. Sarcopenia is discussed in terms of its adverse clinical consequences in older subjects and particularly, in older patients with cancer. Contributions of lifestyle, molecular, and cellular factors are likewise reviewed with suggestions for interventions to improve sarcopenia and its comorbid sequalae.

Induced Fetal Human Muscle Stem Cells with High Therapeutic Potential in a Mouse Muscular Dystrophy Model.

SummaryDuchenne muscular dystrophy (DMD) is a progressive and fatal muscle-wasting disease caused by DYSTROPHIN deficiency. Cell therapy using muscle stem cells (MuSCs) is a potential cure. Here, we report a differentiation method to generate fetal MuSCs from human induced pluripotent stem cells (iPSCs) by monitoring MYF5 expression. Gene expression profiling indicated that MYF5-positive cells in the late stage of differentiation have fetal MuSC characteristics, while MYF5-positive cells in the early stage of differentiation have early myogenic progenitor characteristics. Moreover, late-stage MYF5-positive cells demonstrated good muscle regeneration potential and produced DYSTROPHIN in vivo after transplantation into DMD model mice, resulting in muscle function recovery. The engrafted cells also generated PAX7-positive MuSC-like cells under the basal lamina of DYSTROPHIN-positive fibers. These findings suggest that MYF5-positive fetal MuSCs induced in the late stage of iPSC differentiation have cell therapy potential for DMD.

Slow Your Roll: Inhibiting SETD7 Activity Permits ExVivo Expansion of Muscle Stem Cells.

Muscle stem cell regenerative capacity is rapidly lost during exvivo culture. In this issue of Cell Stem Cell, Judson etal. (2018) show that inhibition of cytoplasmic SETD7, a lysine methyltransferase, potently expands naive, undifferentiated mouse and human muscle stem cells by restricting their progression through the myogenic program.

---Mechanosensitivity of aged muscle stem cells.

ABSTRACTDuring aging, skeletal muscle tissue progressively declines in mass, strength, and regenerative capacity. Decreased muscle stem cell (MuSC) number and impaired function might underlie the aging‐related muscle wasting and impaired regenerative capacity. As yet, the search for factors that regulate MuSC fate and function has revealed several biochemical factors within the MuSC niche that may be responsible for the decline in MuSC regenerative capacity. This decline cannot be explained by environmental factors solely, as the MuSC potential to regenerate muscle tissue is not reversed by changing the biochemical MuSC niche composition. Here we discuss the likeliness that during physical exercise, MuSCs within their niche are subjected to mechanical loads, in particular pressure and shear stress, as well as associated deformations. We postulate that these physical cues are involved in the activation and differentiation of MuSCs as these cells contain several transmembrane sensor proteins that have been shown to be mechanosensitive in other cell types, that is, endothelial cells and osteoprogenitors. We will specifically address age‐related changes in mechanosensing in MuSCs and their niche. Insight in the physical cues applied to the MuSCs in vivo, and how these cues affect MuSC fate and function, helps to develop new therapeutic interventions to counterbalance age‐related muscle loss. This requires an approach combining two‐ and three‐dimensional live cell imaging of MuSCs within contracting muscle tissue, mathematical finite element modeling, and cell biology. © 2017 The Authors. Journal of Orthopaedic Research® Published by Wiley Periodicals, Inc. on behalf of the Orthopaedic Research Society. J Orthop Res 36:632–641, 2018.

Dehydrocorydaline promotes myogenic differentiation via p38MAPK activation.

Muscle regeneration is a coordinated process that involves proliferation and differentiation of muscle progenitor cells. Activation of MyoD is a key event in myogenic differentiation, which is regulated by p38 mitogen-activated protein kinases (MAPK). In a screen of natural compounds for the enhancement of MyoD activity, dehydrocorydaline (DHC) from the Corydalis tuber was identified. Treatment of C2C12 myoblasts with DHC increased the expression levels of muscle-specific proteins, including MyoD, myogenin and myosin heavy chain. In addition, C2C12 myoblasts exhibited enhanced multinucleated myotube formation without any cytotoxicity. Treatment with DHC elevated p38 MAPK activation and the interaction of MyoD with an E protein, which is likely to result in activation of MyoD and promotion of myoblast differentiation. Furthermore, defects in differentiation-induced p38 MAPK activation and myoblast differentiation induced by depletion of the promyogenic receptor protein Cdo in C2C12 myoblasts were restored by DHC treatment. In conclusion, these results indicated that DHC stimulates p38 MAPK activation, which can enhance heterodimerization of MyoD and E proteins, thus resulting in MyoD activation and myoblast differentiation. These findings suggested that DHC may be considered a potential therapeutic compound for the improvement of muscle stem cell regenerative capacity in injured muscle.

Autonomous Extracellular Matrix Remodeling Controls a Progressive Adaptation in Muscle Stem Cell Regenerative Capacity during Development.

Muscle stem cells (MuSCs) exhibit distinct behavior during successive phases of developmental myogenesis. However, how their transition to adulthood is regulated is poorly understood. Here, we show that fetal MuSCs resist progenitor specification and exhibit altered division dynamics, intrinsic features that are progressively lost postnatally. After transplantation, fetal MuSCs expand more efficiently and contribute to muscle repair. Conversely, niche colonization efficiency increases in adulthood, indicating a balance between muscle growth and stem cell pool repopulation. Gene expression profiling identified several extracellular matrix (ECM) molecules preferentially expressed in fetal MuSCs, including tenascin-C, fibronectin, and collagen VI. Loss-of-function experiments confirmed their essential and stagespecific role in regulating MuSC function. Finally, fetal-derived paracrine factors were able to enhance adult MuSC regenerative potential. Together, these findings demonstrate that MuSCs change the way in which they remodel their microenvironment to direct stem cell behavior and support the unique demands of muscle development or repair.

PRMT7 Preserves Satellite Cell Regenerative Capacity.

Regeneration of skeletal muscle requires the continued presence of quiescent muscle stem cells (satellite cells), which become activated in response to injury. Here, we report that whole-body protein arginine methyltransferase PRMT7(-/-) adult mice and mice conditionally lacking PRMT7 in satellite cells using Pax7-CreERT2 both display a significant reduction in satellite cell function, leading to defects in regenerative capacity upon muscle injury. We show that PRMT7 is preferentially expressed in activated satellite cells and, interestingly, PRMT7-deficient satellite cells undergo cell-cycle arrest and premature cellular senescence. These defects underlie poor satellite cell stem cell capacity to regenerate muscle and self-renew after injury. PRMT7-deficient satellite cells express elevated levels of the CDK inhibitor p21CIP1 and low levels of its repressor, DNMT3b. Restoration of DNMT3b in PRMT7-deficient cells rescues PRMT7-mediated senescence. Our findings define PRMT7 as a regulator of the DNMT3b/p21 axis required to maintain muscle stem cell regenerative capacity.