Peripheral Nerve Injury Primes Muscle Stem Cell for Myogenesis by Enhancing Protein Synthesis and Mitochondrial Bioenergetics

Abstract

IntroductionSkeletal muscle has residential muscle stem cells, satellite cells (SC), which are indispensable for skeletal muscle regeneration and homeostasis. Previous studies highlighted the importance of SC microenvironment, or the niche, in controlling SC functions and fates. Among the SC niches, the neuronal inputs from motor neuron (MN) and neuromuscular junction (NMJ) are one of the indispensable factors for functional muscle regeneration after injury. Conversely, a recent study showed that depletion of SC could cause degeneration of NMJ, indicating that SCs also directly contribute to NMJ regeneration (Liu, 2017). However, the underlying mechanisms of SC‐MN communication during muscle regeneration are not well understood. Here, we hypothesized that the SC‐MN interaction enhances regeneration of damaged muscle by increasing myogenesis, protein synthesis, and mitochondrial function.Materials and MethodsGeorgia Tech Animal Care and Use Committee had reviewed and approved all animal procedures. Denervation (DEN) was performed on the sciatic nerves of young (3~5 months) and old (20~ months) C57BL/6, as well as mdx (a mouse model of DMD) by pinching them. The contralateral side was served as the control. SCs were isolated by FACS from DEN and the control muscles to compare RNA and protein expressions, proliferation, myogenesis, and cellular bioenergetics. Moreover, the in vivo regeneration and SC transplant capacities were tested.Results and DiscussionThe Wallerian degeneration of MN was evident up to post‐DEN day 7 (Figure 1a). Although the DEN muscle weight was decreased, the number of SC increased by 1.5‐fold at post‐DEN day 7 in young muscle (Figure 1b). In addition to the number of the SCs, we observed significant alteration of gene expression patterns after DEN. Specifically, genes associated with SC markers, cell cycle, and myogenesis were up‐regulated in young DEN muscle. In parallel, we observed significantly enhanced myogenesis of the SCs, which was also confirmed in vitro by proliferation, differentiation, and myogenic colony formation. As the myogenesis is energy demanding process, it was accompanied with the increased mitochondrial bioenergetics. Furthermore, the synergistic effect of the SC‐MN interaction was supported by increased in vivo regeneration after muscle/nerve injury and engraftment of transplanted SC. Interestingly, SC‐MN synergy observed in young was abolished in aged or mdx which have fragmented NMJs. It is suggesting that the lack of the regenerative capacity in these muscles is partially due to the abnormality in SC‐MN interaction (Figure 1b and c).ConclusionAll in all, our data show that the SC‐MN interaction synergistically enhances functional regeneration after skeletal muscle injury and depletion of this crosstalk may cause the lack of regeneration as shown in aged and mdx muscle.Support or Funding InformationS&R Foundation Ryuji Ueno Award (YCJ), NIH R21AR072287 (YCJ)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.