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    Cellular and Molecular Bioengineering

    (F-229) Transplantation of muscle stem cell mitochondria augments the bioenergetic function of dystrophic muscle in mice

    Thursday, October 12, 2023
    9:30 AM – 10:30 AM PDT
    Location: Exhibit Hall - Row F - Poster # 229
    Introduction:: Mitochondrial dysfunction has been implicated in a variety of pathologies, including muscular dystrophies. Intriguingly, a remnant from the endosymbiotic mitochondrial origin theory, recent evidence suggests that mitochondria retain the ability to transfer intercellularly, and mitochondrial transplantation has been explored as a potential means for therapeutic intervention. During muscle regeneration, resident stem cells, also known as muscle satellite cells (MuSCs), undergo myogenic differentiation and fusion to form de novo myofibers or fuse with existing multinucleated myofibers. Leveraging this cell-cell fusion process, we postulated that donor MuSC mitochondria can be transferred to host muscle during muscle repair.

    Materials and Methods:: MuSCs purified from mitochondrial reporter transgenic mice were transplanted into dystrophic host muscle. Single muscle fibers isolated from the host were imaged using confocal microscopy to assess mitochondrial network (reticulum) and myonuclei organization. Both mtDNA and nuclear-encoded mitochondrial gene expression were evaluated using qPCR, while oxygen consumption and ATP production rates were measured using Seahorse and Oroboros.

    Results, Conclusions, and Discussions:: Here, we report that when healthy donor MuSCs are purified and transplanted into dystrophic host muscle, mitochondrial network (reticulum) and bioenergetic function can be significantly enhanced. By transplanting MuSCs purified from mitochondrial reporter transgenic mice, we first demonstrate remodeling of the mitochondrial reticulum following MuSC fusion into the host myofiber. Specifically, myonuclei originating from fused MuSCs were adjacent to high densities of mitochondrial content, implying these MuSC-derived myonuclei regulate synthesis of mitochondria. To support this, mtDNA copy number and nuclear-encoded mitochondrial gene expression were upregulated following MuSC transplantation, further indicating MuSC-driven mitochondrial biogenesis. Along with increased mitochondrial content in transplanted muscle, we also report augmented mitochondrial function measured by greater oxygen consumption and ATP production rates in isolated single myofibers. Furthermore, when bioenergetically-enriched (exercised) donor MuSCs were transplanted, improvements in mitochondrial content and bioenergetic function were also observed. Conversely, these improvements were abrogated when we transplanted MuSCs with defective mitochondria. Overall, these data provide a novel approach to transfer mitochondria to pathological skeletal muscle in order to assist muscle function and regeneration.

    Acknowledgements (Optional): : NIH National Institute of Arthritis and Musculoskeletal and Skin Disease, Regenerative Engineering and Medicine

    References (Optional): :