The roles of muscle stem cells in muscle injury, atrophy and hypertrophy

Aging of population brings related social problems, such as muscle attenuation and regeneration barriers with increased aging. Muscle repair and regeneration depend on muscle stem cells (MuSCs). Obstructive sleep apnea (OSA) rises in the aging population. OSA leads to hypoxia and upper airway muscle injury. However, little is known about the effect of increasing age and hypoxia to the upper airway muscle. The genioglossus (GG) is the major dilator muscle to keep the upper airway open. Here, we reported that muscle fiber and MuSC function declined with aging in GG. Increasing age also decreased the migration and proliferation of GG MuSCs. p53 and p21 were high expressions both in muscle tissue and in GG MuSCs. We further found that hypoxia inhibited GG MuSC proliferation and decreased myogenic differentiation. Then, hypoxia enhanced the inhibition effect of aging to proliferation and differentiation. Finally, we investigated that hypoxia and aging interact to form a vicious circle with upregulation of p53 and p21. This vicious hypoxia plus aging damage accelerated upper airway muscle injury. Aging and hypoxia are the major damage elements in OSA patients, and we propose that the damage mechanism of hypoxia and aging in GG MuSCs will help to improve upper airway muscle regeneration.

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Injury-mediated stiffening persistently activates muscle stem cells through YAP and TAZ mechanotransduction

Science Advances ◽

10.1126/sciadv.abe4501 ◽

2021 ◽

Vol 7 (11) ◽

pp. eabe4501

Author(s):

Jason S. Silver ◽

K. Arda Günay ◽

Alicia A. Cutler ◽

Thomas O. Vogler ◽

Tobin E. Brown ◽

...

Keyword(s):

Skeletal Muscle ◽

Stem Cells ◽

Muscle Injury ◽

Muscle Stiffness ◽

Post Injury ◽

Muscle Stem Cells ◽

Transcription Regulator

The skeletal muscle microenvironment transiently remodels and stiffens after exercise and injury, as muscle ages, and in myopathic muscle; however, how these changes in stiffness affect resident muscle stem cells (MuSCs) remains understudied. Following muscle injury, muscle stiffness remained elevated after morphological regeneration was complete, accompanied by activated and proliferative MuSCs. To isolate the role of stiffness on MuSC behavior and determine the underlying mechanotransduction pathways, we cultured MuSCs on strain-promoted azide-alkyne cycloaddition hydrogels capable of in situ stiffening by secondary photocrosslinking of excess cyclooctynes. Using pre- to post-injury stiffness hydrogels, we found that elevated stiffness enhances migration and MuSC proliferation by localizing yes-associated protein 1 (YAP) and WW domain–containing transcription regulator 1 (WWTR1; TAZ) to the nucleus. Ablating YAP and TAZ in vivo promotes MuSC quiescence in postinjury muscle and prevents myofiber hypertrophy, demonstrating that persistent exposure to elevated stiffness activates mechanotransduction signaling maintaining activated and proliferating MuSCs.

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Met and Cxcr4 cooperate to protect skeletal muscle stem cells against inflammation-induced damage during regeneration

eLife ◽

10.7554/elife.57356 ◽

2021 ◽

Vol 10 ◽

Author(s):

Ines Lahmann ◽

Joscha Griger ◽

Jie-Shin Chen ◽

Yao Zhang ◽

Markus Schülke ◽

...

Keyword(s):

Skeletal Muscle ◽

Stem Cells ◽

Neutralizing Antibodies ◽

Muscle Injury ◽

Inflammatory Cells ◽

Protective Role ◽

Muscle Repair ◽

Muscle Stem Cells ◽

Genetic Ablation ◽

Injury Models

Acute skeletal muscle injury is followed by an inflammatory response, removal of damaged tissue, and the generation of new muscle fibers by resident muscle stem cells, a process well characterized in murine injury models. Inflammatory cells are needed to remove the debris at the site of injury and provide signals that are beneficial for repair. However, they also release chemokines, reactive oxygen species as well as enzymes for clearance of damaged cells and fibers, which muscle stem cells have to withstand in order to regenerate the muscle. We show here that MET and CXCR4 cooperate to protect muscle stem cells against the adverse environment encountered during muscle repair. This powerful cyto-protective role was revealed by the genetic ablation of Met and Cxcr4 in muscle stem cells of mice, which resulted in severe apoptosis during early stages of regeneration. TNFα neutralizing antibodies rescued the apoptosis, indicating that TNFα provides crucial cell-death signals during muscle repair that are counteracted by MET and CXCR4. We conclude that muscle stem cells require MET and CXCR4 to protect them against the harsh inflammatory environment encountered in an acute muscle injury.

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