Sympathetic activity is correlated with satellite cell aging and myogenesis via β2-adrenoceptor

Abstract Background and objective 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. 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 methods To 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. Results The 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. Conclusion Normal 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.

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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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Skeletal muscle repair by adult human mesenchymal stem cells from synovial membrane

The Journal of Cell Biology ◽

10.1083/jcb.200212064 ◽

2003 ◽

Vol 160 (6) ◽

pp. 909-918 ◽

Cited By ~ 323

Author(s):

Cosimo De Bari ◽

Francesco Dell'Accio ◽

Frank Vandenabeele ◽

Joris R. Vermeesch ◽

Jean-Marc Raymackers ◽

...

Keyword(s):

Skeletal Muscle ◽

Stem Cells ◽

Mesenchymal Stem Cells ◽

Mouse Model ◽

Nude Mouse ◽

Synovial Membrane ◽

Myogenic Differentiation ◽

Muscle Repair ◽

Mouse Muscle ◽

Adult Human

We have demonstrated previously that adult human synovial membrane-derived mesenchymal stem cells (hSM-MSCs) have myogenic potential in vitro (De Bari, C., F. Dell'Accio, P. Tylzanowski, and F.P. Luyten. 2001. Arthritis Rheum. 44:1928–1942). In the present study, we have characterized their myogenic differentiation in a nude mouse model of skeletal muscle regeneration and provide proof of principle of their potential use for muscle repair in the mdx mouse model of Duchenne muscular dystrophy. When implanted into regenerating nude mouse muscle, hSM-MSCs contributed to myofibers and to long term persisting functional satellite cells. No nuclear fusion hybrids were observed between donor human cells and host mouse muscle cells. Myogenic differentiation proceeded through a molecular cascade resembling embryonic muscle development. Differentiation was sensitive to environmental cues, since hSM-MSCs injected into the bloodstream engrafted in several tissues, but acquired the muscle phenotype only within skeletal muscle. When administered into dystrophic muscles of immunosuppressed mdx mice, hSM-MSCs restored sarcolemmal expression of dystrophin, reduced central nucleation, and rescued the expression of mouse mechano growth factor.

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Stem Cells for the Treatment of Skeletal Muscle Injury

Clinics in Sports Medicine ◽

10.1016/j.csm.2008.08.009 ◽

2009 ◽

Vol 28 (1) ◽

pp. 1-11 ◽

Cited By ~ 57

Author(s):

Andres J. Quintero ◽

Vonda J. Wright ◽

Freddie H. Fu ◽

Johnny Huard

Keyword(s):

Skeletal Muscle ◽

Stem Cells ◽

Muscle Injury ◽

Skeletal Muscle Injury

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Therapeutic potential of adipose-derived stem cells and macrophages for ischemic skeletal muscle repair

Regenerative Medicine ◽

10.2217/rme-2016-0094 ◽

2017 ◽

Vol 12 (2) ◽

pp. 153-167 ◽

Cited By ~ 13

Author(s):

Viktoriya Rybalko ◽

Pei-Ling Hsieh ◽

Laura M Ricles ◽

Eunna Chung ◽

Roger P Farrar ◽

...

Keyword(s):

Skeletal Muscle ◽

Stem Cells ◽

Therapeutic Potential ◽

Adipose Derived Stem Cells ◽

Muscle Repair

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Coaxing stem cells for skeletal muscle repair

Advanced Drug Delivery Reviews ◽

10.1016/j.addr.2014.07.007 ◽

2015 ◽

Vol 84 ◽

pp. 198-207 ◽

Cited By ~ 23

Author(s):

Karl J.A. McCullagh ◽

Rita C.R. Perlingeiro

Keyword(s):

Skeletal Muscle ◽

Stem Cells ◽

Muscle Repair

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Emerging drugs for treating skeletal muscle injury and promoting muscle repair

Expert Opinion on Emerging Drugs ◽

10.1517/14728214.2010.524743 ◽

2011 ◽

Vol 16 (1) ◽

pp. 163-182 ◽

Cited By ~ 12

Author(s):

Stefan M Gehrig ◽

Gordon S Lynch

Keyword(s):

Skeletal Muscle ◽

Muscle Injury ◽

Muscle Repair ◽

Skeletal Muscle Injury

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Interleukin-6 promotes myogenic differentiation of mouse skeletal muscle cells: role of the STAT3 pathway

AJP Cell Physiology ◽

10.1152/ajpcell.00025.2012 ◽

2013 ◽

Vol 304 (2) ◽

pp. C128-C136 ◽

Cited By ~ 55

Author(s):

Miriam Hoene ◽

Heike Runge ◽

Hans Ulrich Häring ◽

Erwin D. Schleicher ◽

Cora Weigert

Keyword(s):

Skeletal Muscle ◽

Mrna Expression ◽

Myogenic Differentiation ◽

Muscle Cells ◽

C2c12 Cells ◽

Skeletal Muscle Cells ◽

Wild Type ◽

C2c12 Myoblasts ◽

Sequence Of Events ◽

Primary Mouse

Myogenic differentiation of skeletal muscle cells is characterized by a sequence of events that include activation of signal transducer and activator of transcription 3 (STAT3) and enhanced expression of its target gene Socs3. Autocrine effects of IL-6 may contribute to the activation of the STAT3-Socs3 cascade and thus to myogenic differentiation. The importance of IL-6 and STAT3 for the differentiation process was studied in C2C12 cells and in primary mouse wild-type and IL-6−/− skeletal muscle cells. In differentiating C2C12 myoblasts, the upregulation of IL-6 mRNA expression and protein secretion started after increased phosphorylation of STAT3 on tyrosine 705 and increased mRNA expression of Socs3 was observed. Knockdown of STAT3 and IL-6 mRNA in differentiating C2C12 myoblasts impaired the expression of the myogenic markers myogenin and MyHC IIb and subsequently myotube fusion. However, the knockdown of IL-6 did not prevent the induction of STAT3 tyrosine phosphorylation. The IL-6-independent activation of STAT3 was verified in differentiating primary IL-6−/− myoblasts. The phosphorylation of STAT3 and the expression levels of STAT3, Socs3, and myogenin during differentiation were comparable in the primary myoblasts independent of the genotype. However, IL-6−/− cells failed to induce MyHC IIb expression to the same level as in wild-type cells and showed reduced myotube formation. Supplementation of IL-6 could partially restore the fusion of IL-6−/− cells. These data demonstrate that IL-6 depletion during myogenic differentiation does not reduce the activation of the STAT3-Socs3 cascade, while IL-6 and STAT3 are both necessary to promote myotube fusion.

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