Meakins-Christie Laboratories, Translational Research in Respiratory Diseases Program, Research Institute of the McGill University Health Centre, Montréal, QC, Canada.
Department of Critical Care, McGill University Health Centre, Montréal, QC, Canada.
Nat Commun. 2023 Mar 2;14(1):1199. doi: 10.1038/s41467-023-36817-1.
Autophagy is a critical process in the regulation of muscle mass, function and integrity. The molecular mechanisms regulating autophagy are complex and still partly understood. Here, we identify and characterize a novel FoxO-dependent gene, d230025d16rik which we named Mytho (Macroautophagy and YouTH Optimizer), as a regulator of autophagy and skeletal muscle integrity in vivo. Mytho is significantly up-regulated in various mouse models of skeletal muscle atrophy. Short term depletion of MYTHO in mice attenuates muscle atrophy caused by fasting, denervation, cancer cachexia and sepsis. While MYTHO overexpression is sufficient to trigger muscle atrophy, MYTHO knockdown results in a progressive increase in muscle mass associated with a sustained activation of the mTORC1 signaling pathway. Prolonged MYTHO knockdown is associated with severe myopathic features, including impaired autophagy, muscle weakness, myofiber degeneration, and extensive ultrastructural defects, such as accumulation of autophagic vacuoles and tubular aggregates. Inhibition of the mTORC1 signaling pathway in mice using rapamycin treatment attenuates the myopathic phenotype triggered by MYTHO knockdown. Skeletal muscles from human patients diagnosed with myotonic dystrophy type 1 (DM1) display reduced Mytho expression, activation of the mTORC1 signaling pathway and impaired autophagy, raising the possibility that low Mytho expression might contribute to the progression of the disease. We conclude that MYTHO is a key regulator of muscle autophagy and integrity.
自噬是调节肌肉质量、功能和完整性的关键过程。调节自噬的分子机制复杂，部分仍未被理解。在这里，我们鉴定并描述了一个新的 FoxO 依赖性基因 d230025d16rik，我们将其命名为 Mytho（Macroautophagy and YouTH Optimizer），作为体内自噬和骨骼肌完整性的调节剂。Mytho 在各种骨骼肌萎缩的小鼠模型中显著上调。在小鼠中短期消耗 Mytho 可减轻饥饿、去神经、癌症恶病质和脓毒症引起的肌肉萎缩。虽然 MYTHO 过表达足以引发肌肉萎缩，但 MYTHO 敲低导致肌肉质量逐渐增加，同时 mTORC1 信号通路持续激活。长时间的 MYTHO 敲低与严重的肌病特征相关，包括自噬受损、肌肉无力、肌纤维退化以及广泛的超微结构缺陷，如自噬空泡和管状聚集体的积累。使用雷帕霉素抑制小鼠中的 mTORC1 信号通路可减轻由 MYTHO 敲低引发的肌病表型。诊断为 1 型肌强直性营养不良（DM1）的人类患者的骨骼肌显示 Mytho 表达降低、mTORC1 信号通路激活和自噬受损，这提示 Mytho 表达降低可能导致疾病进展。我们的结论是，MYTHO 是肌肉自噬和完整性的关键调节剂。
