Elrefaei Eman, Yamazaki Satoru, Yazawa Issei, Takahashi Yusuke, Ito Naoki, Hayashiji Nozomi, Nishida Yuya, Nishino Ichizo, Takashima Seiji, Shintani Yasunori
Department of Molecular Pharmacology, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.
Department of Medical Biochemistry, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
FASEB J. 2025 Jun 30;39(12):e70609. doi: 10.1096/fj.202402152R.
In addition to the canonical metabolism-regulating function, Adenosine monophosphate-activated protein kinase (AMPK) has noncanonical functions, in which AMPK spatiotemporally phosphorylates specific sets of substrates. Recently, we identified LSMEM2, a novel substrate of AMPK in the heart. LSMEM2 is a membrane protein localized at the intercalated disc (ICD), whose function is currently under investigation. Interestingly, LSMEM2 is also expressed in the skeletal muscles. As skeletal muscles lack a homophilic intercellular junction corresponding to the ICD in the heart, predicting the role of LSMEM2 in skeletal muscles is difficult. In this study, we identified that LSMEM2 is expressed in skeletal muscles, specifically at the neuromuscular junction (NMJ). LSMEM2-knockout mice showed no histological abnormalities, suggesting that LSMEM2 is not essential for skeletal muscle development. The overexpression of full-length wild-type or C-del mutant of LSMEM2 led to the tubular aggregate formation with functional abnormality in male mice. RNA sequence analysis revealed that the gene sets of mitochondrial oxidative phosphorylation and vesicle-mediated transport are enriched in LSMEM2 overexpression. Furthermore, histological analysis demonstrated the accumulation of swollen subsarcolemmal mitochondria in LSMEM2-overexpressing skeletal muscles. The study findings suggest that LSMEM2 may play a role in the pathogenesis of skeletal muscle diseases.
除了典型的代谢调节功能外，单磷酸腺苷激活的蛋白激酶（AMPK）还具有非典型功能，即AMPK在时空上磷酸化特定的底物组。最近，我们在心脏中鉴定出LSMEM2是AMPK的一种新底物。LSMEM2是一种定位在闰盘（ICD）的膜蛋白，其功能目前正在研究中。有趣的是，LSMEM2在骨骼肌中也有表达。由于骨骼肌缺乏与心脏中ICD相对应的同源性细胞间连接，因此很难预测LSMEM2在骨骼肌中的作用。在本研究中，我们发现LSMEM2在骨骼肌中表达，特别是在神经肌肉接头（NMJ）处。LSMEM2基因敲除小鼠未表现出组织学异常，这表明LSMEM2对骨骼肌发育不是必需的。LSMEM2全长野生型或C端缺失突变体的过表达导致雄性小鼠形成具有功能异常的管状聚集体。RNA序列分析显示，线粒体氧化磷酸化和囊泡介导运输的基因集在LSMEM2过表达中富集。此外，组织学分析表明，LSMEM2过表达的骨骼肌中肌膜下肿胀线粒体积累。研究结果表明，LSMEM2可能在骨骼肌疾病的发病机制中起作用。
