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Current study demonstrated the impact of heat therapy on skeletal muscle function in a model of Duchenne muscular dystrophy (DMD). The aim of this study was to: (1) examine the impact of treatment temperature on the skeletal muscle adaptation in DBA/2J mice; and (2) determine the impact of repeated HT for 3 consecutive weeks on body composition and skeletal muscle function in D2.mdx, a model of DMD. From study 1, we revealed that HT at 39℃ for 3 weeks significantly promoted relative muscle mass of both EDL and soleus muscle in DBA/2J mice. However, from study 2, HT at 39℃ for 3 weeks does not improve muscle function or increase muscle mass in a mouse model of DMD.

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Previous work from our laboratory in the mdx mouse model of Duchenne muscular dystrophy (DMD) demonstrated that a fraction of muscle stem cells (i.e., satellite cells) (MuSCs) progressively lose the expression of myogenic markers during the progression of the disease. In the process of characterizing this aberrant behaviour, we serendipitously discovered that MuSCs might be separated into two distinct subpopulations based on the expression of the GPI-anchored surface protein CD90. Crucially, this separation does not correlate with a divergence from the myogenic lineage; instead, it separates the pool of MuSCs into two subpopulations, both maintaining myogenic properties in healthy muscles. These two newly identified subpopulations do not overlap with any previously reported subpopulation and may be prospectively isolated; present a different response in terms of kinetics of activation and differentiation during the regenerative process induced by acute muscle damage; show a different propensity to enter in GAlert state upon distal injury; display dissimilar pAMPK activity and contain a different amount of mitochondria; are present in different proportions in distinct muscle groups; differentially express ECM encoding genes during quiescence. Moreover, one of the two subpopulations can give rise to the other and therefore appears to be upstream in the lineage hierarchy. Notably, loss of function experiments, in which CD90 was downregulated in MuSCs, diminish the difference in activation displayed by the two subpopulations. This demonstrates that CD90 is a molecular determinant of MuSCs functional diversification. Importantly, although the two subpopulations of MuSCs are numerically similar in healthy limb muscles, one of the two subpopulations is lost with time in dystrophic mdx mice. Based on these data, we are hypothesizing that an imbalance between the two newly identified subpopulations may impair regeneration in the dystrophic muscles. These observations not only increase our knowledge of the molecular and cellular dynamics that are controlling normal and pathological muscle homeostasis but also open the possibility that restoring the proper functional equilibrium between subpopulations of MuSCs may counteract the progression of the dystrophic disease.

Glucocorticoids are the most widely prescribed medications due primarily to their anti-inflammatory and immunosuppressive actions, however, their use is not without side effects. Among these, glucocorticoids cause profound muscle atrophy, yet paradoxically are used as the first line of treatment for muscle wasting disorders such as Duchenne Muscular Dystrophy (DMD) and inflammatory myopathies. In DMD patients, glucocorticoid treatment can improve muscle strength during the first 6 months of treatment and can delay loss of muscle function by up to three years. While recent advancements have been made to understand the effect of glucocorticoids (GCs) on the myofiber, the impact of GCs on skeletal muscle stem cells (MuSCs), the adult stem cells responsible for muscle regeneration, and their role in myogenic differentiation, are relatively unknown. To study the role of glucocorticoid signalling during muscle repair, I developed a conditional null mouse (GRMuSC-/-) model in which glucocorticoid receptor (GR) expression is knocked out specifically in MuSCs (GRMuSC-/-). One-week following acute muscle injury, WT and GRMuSC-/- mice both underwent robust repair assessed by myofiber cross-sectional area (CSA) analysis. However, the GR-/- MuSCs failed to return to quiescence following repair resulting in a significant increase in average myofiber CSA at 28- and 42- days post-injury, as compared to controls. Loss of the GR led to a significant increase in the percentage of PAX7+Ki67+ cycling cells in GRMuSC-/- mice (as compared to controls) at 42 days post injury. In the uninjured contralateral limb, I observed significantly fewer MuSCs in GRMuSC-/- mice with a concomitant increase in fibers with centrally located nuclei, indicating that these PAX7+ MuSCs progressed to differentiation in the absence of direct injury. In an uninjured model, two weeks following loss of GR expression there was an increase in the percentage of BrdU+ and Ki67+ cycling cells in resting GRMuSC-/- tibialis anterior muscles as compared to WT, suggesting that the GR acts to maintain MuSC quiescence. Consistent with this, immunostaining of single EDL myofiber fibers at T2h post-dissociation revealed that loss of GR in MuSCs lead to precocious activation and subsequent proliferation of MuSCs as compared to controls. Bulk RNA-sequencing from in situ fixed MuSCs in resting muscle revealed that the gene signature of GR-/- MuSCs was consistent with cells that have exited from the quiescent state and are activated for differentiation. Despite precocious activation, GR-/- myoblasts differentiate and fuse normally, however the myotubes produced had abnormal morphology and aberrant myonuclear placement in regenerated muscle fibers in vivo.

付記する学位プログラム名: 京都大学卓越大学院プログラム「メディカルイノベーション大学院プログラム」 / 京都大学 / 新制・課程博士 / 博士(医科学) / 甲第25007号 / 医科博第154号 / 新制||医科||10(附属図書館) / 京都大学大学院医学研究科医科学専攻 / (主査)教授 遊佐 宏介, 教授 萩原 正敏, 教授 齋藤 潤 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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