The CMRD gene SAR1B regulates mitochondria metabolism in skeletal muscle
Wenjing Zhou1, Chenxin Wang2, Dong Huang1, Li Quan1, and Xiao-Wei Chen1,2 From 1Institute of Molecular Medicine, 2PKU-THU Center for Life Sciences, Peking University, China
The mitochondria in muscle cells form numerous membrane contacts the sarcoplasmic reticulum (SR), which organizes into an elaborated membrane network. The unique structure maximizes the transmission of calcium signaling for excitation-contraction coupling and other functions of the muscle. However, the mechanism to establish and regulate these membrane contacts remains elusive. Here we show that the GTPase SAR1B, best understood in the regulation of the COPII vesicle formation from the endoplasmic reticulum, plays a previously unknown function in skeletal muscle. SAR1B is highly enriched in mouse and human skeletal muscle tissues. Muscle specific knockout of SAR1B causes centronuclear myopathy and elevated serum creatine kinase levels in mice. The SAR1B-deficient mice show impaired muscle performance and mitochondria function. Surprisingly, loss of SAR1B in muscle increases SR-mitochondria contacts, with altered proteome and lipidome. Consequently, SAR1B KO myocytes display impaired mitochondrial calcium signaling and cellular energetics. Taken together, the data may explain the unexpected myopathy observed in human patients with CMRD (Chylomicron Retention Disease) caused by SAR1B mutations, and further a previously unrecognized role of SAR1B to coordinate cell metabolism with muscle function.
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