SEPN1-related myopathy (SEPN1-RM) is a muscle disorder due to mutations of the SEPN1 gene, which is characterized by muscle weakness and fatigue leading to scoliosis and life-threatening respiratory failure. Core lesions, focal areas of mitochondria depletion in skeletal muscle fibers, are the most common histopathological lesion. SEPN1-RM underlying mechanisms and the precise role of SEPN1 in muscle remained incompletely understood, hindering the development of biomarkers and therapies for this untreatable disease. To investigate the pathophysiological pathways in SEPN1-RM, we performed metabolic studies, calcium and ATP measurements, super-resolution and electron microscopy on in vivo and in vitro models of SEPN1 deficiency as well as muscle biopsies from SEPN1-RM patients. Mouse models of SEPN1 deficiency showed marked alterations in mitochondrial physiology and energy metabolism, suggesting that SEPN1 controls mitochondrial bioenergetics. Moreover, we found that SEPN1 was enriched at the mitochondria-associated membranes (MAM), and was needed for calcium transients between ER and mitochondria, as well as for the integrity of ER-mitochondria contacts. Consistently, loss of SEPN1 in patients was associated with alterations in body composition which correlated with the severity of muscle weakness, and with impaired ER-mitochondria contacts and low ATP levels. Our results indicate a role of SEPN1 as a novel MAM protein involved in mitochondrial bioenergetics. They also identify a systemic bioenergetic component in SEPN1-RM and establish mitochondria as a novel therapeutic target. This role of SEPN1 contributes to explain the fatigue and core lesions in skeletal muscle as well as the body composition abnormalities identified as part of the SEPN1-RM phenotype. Finally, these results point out to an unrecognized interplay between mitochondrial bioenergetics and ER homeostasis in skeletal muscle. They could therefore pave the way to the identification of biomarkers and therapeutic drugs for SEPN1-RM and for other disorders in which muscle ER-mitochondria cross-talk are impaired.

SEPN1 相关肌病 (SEPN1-RM) 是一种由SEPN1突变引起的肌肉疾病基因，其特征是肌肉无力和疲劳，导致脊柱侧弯和危及生命的呼吸衰竭。核心病变，骨骼肌纤维中线粒体耗竭的焦点区域，是最常见的组织病理学病变。SEPN1-RM 的潜在机制和 SEPN1 在肌肉中的确切作用仍未完全了解，阻碍了这种无法治愈的疾病的生物标志物和疗法的开发。为了研究 SEPN1-RM 的病理生理学途径，我们对 SEPN1 缺乏症的体内和体外模型以及来自 SEPN1-RM 患者的肌肉活检进行了代谢研究、钙和 ATP 测量、超分辨率和电子显微镜检查。SEPN1 缺陷的小鼠模型显示线粒体生理和能量代谢的显着改变，表明 SEPN1 控制线粒体生物能学。此外，我们发现 SEPN1 在线粒体相关膜 (MAM) 处富集，并且是 ER 和线粒体之间的钙瞬变以及 ER-线粒体接触的完整性所必需的。一致地，患者中 SEPN1 的缺失与身体成分的改变有关，而身体成分的改变与肌肉无力的严重程度、内质网-线粒体接触受损和 ATP 水平低有关。我们的结果表明 SEPN1 作为参与线粒体生物能量学的新型 MAM 蛋白的作用。他们还确定了 SEPN1-RM 中的全身生物能成分，并将线粒体作为一种新的治疗靶点。SEPN1 的这种作用有助于解释骨骼肌中的疲劳和核心损伤，以及被确定为 SEPN1-RM 表型一部分的身体成分异常。最后，这些结果指出了线粒体生物能学和骨骼肌内质网稳态之间的相互作用。因此，他们可以为 SEPN1-RM 和其他肌肉 ER-线粒体串扰受损的疾病的生物标志物和治疗药物的鉴定铺平道路。