Beschreibung:
INTRODUCTION: Skeletal muscle homeostasis is maintained by resident stem cells, called muscle satellite cells (MuSCs). Similar to other adult stem cells, MuSC function is coordinated by the cellular and acellular components of their microenvironment, or niche. While the processes that couple neurotransmission and muscle contraction have been well characterized, little is known about the reciprocal crosstalk between neural network and MuSCs. We postulated that nerve injury coupled with stem cell transplantation would enrich MuSC function in muscle regeneration. METHODS: To induce peripheral nerve injury, we used sciatic nerve pinch, in which epineurium is intact, in C57BL6 mice. Following seven days of nerve injury, MuSCs were purified using FACS. A combination of in vitro proliferation, differentiation, in vivo muscle regeneration, MuSC transplantation, immunofluorescence, gene expression, and protein analyses were performed to assess differences in myogenesis. In addition, denervation response in aged (22 – 24 months) mice and a mouse model of Duchenne muscular dystrophy ( mdx) were compared to that of young (2 – 4 months) mice. RESULTS AND DISCUSSION: After seven days of mild peripheral nerve perturbation, we observed a significant increase in Pax7+ MuSC bioavailability as well as augmented myogenesis, as measured by proliferation, differentiation, and fusion in vitro. This enhancement in myogenesis was correlated with an increase in mitochondrial biogenesis, mitochondrial dynamics, and mitochondrial oxidative metabolism. Moreover, MuSCs from denervated muscle displayed a significant increase in the protein synthesis pathway. We further validated synergistic interactions between nerve and MuSCs using transplantation experiments. Both as donors and recipients, nerve injured MuSCs showed a significant increase in transplantation efficiency. However, chronic disruption or degeneration of the neuromuscular junction (NMJ) that occurs in muscular dystrophy and with biological aging diminishes the MuSC-motor unit interactions, causing significant deficits in muscle regeneration. Overall, these results underscore the importance of NMJs and the neural network as essential components of the MuSC niche. SIGNIFICANCE/CLINICAL RELEVANCE: Determining the significance of MuSC-nerve interactions and their functional outcomes, as well as the possibility of modulating these connections, would have important implications for understanding neuromuscular disease pathology and developing new therapeutic interventions. REFERENCES: [1] Larouche JA et al. eLife https://doi.org/10.7554/eLife.66749 This work was supported by the National Institute of Health under award number (R01AG072309, R21AR072287) and Department of Defense under award number W81XWH-20-1-0336. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.