Abstract
Background and objectiveSympathetic activity plays an important role in the proliferation and differentiation of stem cells, and it changes over time, thereby exerting differential effects on various stem cell types. Aging causes sympathetic hyperactivity in aged tissues and blunts sympathetic nerves regulation, and sympathetic abnormalities play a role in aging-related diseases. Currently, the effect of sympathetic activity on skeletal muscle stem cells, namely satellite cells (SCs), is unclear. This study aimed to investigate the effects of skeletal muscle sympathetic activity on SC aging and skeletal muscle repair.Materials and methodsTo evaluate skeletal muscle and fibrotic areas, numbers of SCs and myonuclei per muscle fiber, β2-adrenoceptor (β2-ADR) expression, muscle repair, and sympathetic innervation in skeletal muscle, aged mice, young mice that underwent chemical sympathectomy (CS) were utilized. Mice with a tibialis anterior muscle injury were treated by barium chloride (BaCl2) and clenbuterol (CLB) in vivo. SCs or C2C12 cells were differentiated into myotubes and treated with or without CLB. Immunofluorescence, western blot, sirius red, and hematoxylin–eosin were used to evaluate SCs, myogenic repair and differentiation.ResultsThe number of SCs, sympathetic activity, and reparability of muscle injury in aged mice were significantly decreased, compared with those in young mice. The above characteristics of young mice that underwent CS were similar to those of aged mice. While CLB promoted the repair of muscle injury in aged and CS mice and ameliorated the reduction in the SC number and sympathetic activity, the effects of CLB on the SCs and sympathetic nerves in young mice were not significant. CLB inhibited the myogenic differentiation of C2C12 cells in vitro. We further found that NF-κB and ERK1/2 signaling pathways were activated during myogenic differentiation, and this process could be inhibited by CLB.ConclusionNormal sympathetic activity promoted the stemness of SCs to thereby maintain a steady state. It also could maintain total and self-renewing number of SCs and maintain a quiescent state, which was correlated with skeletal SCs via β2-ADR. Normal sympathetic activity was also beneficial for the myogenic repair of injured skeletal muscle.
Highlights
Skeletal muscles have a good regeneration ability due to the existence of skeletal muscle stem cells, namely muscle satellite cells (SCs)
We further found that nuclear factor-κB (NF-κB) and Extracellular signal regulated kinase 1⁄2 (ERK1/2) signaling pathways were activated during myogenic differentiation, and this process could be inhibited by CLB
Skeletal muscle fibrosis was increased, while the number of SCs and sympathetic activity were decreased in aged mice First, we found that muscle cells of the young mice were more compact, with larger area of the muscle cells, and lower proportion of fibrous tissue, compared with the aged mice (Fig. 1A–C)
Summary
Skeletal muscles have a good regeneration ability due to the existence of skeletal muscle stem cells, namely muscle satellite cells (SCs). MyoD and Myf can induce the expression of key transcription factors, such as myogenin, which can promote the differentiation of SCs/progenitor cells. Myf5(−) SCs are self-renewing skeletal muscle stem cells, while Myf5(+) cells represent differentiated skeletal muscle progenitor cells [7]. Sympathetic activity plays an important role in the proliferation and differentiation of stem cells, and it changes over time, thereby exerting differential effects on various stem cell types. The effect of sympathetic activity on skeletal muscle stem cells, namely satellite cells (SCs), is unclear. This study aimed to investigate the effects of skeletal muscle sympathetic activity on SC aging and skeletal muscle repair
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