Muscle regulates mTOR dependent axonal local translation in motor neurons via CTRP3 secretion: implications for a neuromuscular disorder, spinal muscular atrophy

Spinal muscular atrophy( SMA) is an inherited neuromuscular disorder, which causes dysfunction/loss of lower motor neuronsand muscle weaknessas well as atrophy. While SMAis primarily considered as a motor neuron disease, recent data suggests that survival motor neuron(SMN) deficiency in muscle causes intrinsic defects. We systematically profiled secreted proteins from control and SMN deficient muscle cells with two combined metabolic labeling methods and mass spectrometry. From the screening, we found lower levels of C1q/TNF-related protein 3 (CTRP3) in the SMAmuscle secretomeand confirmed that CTRP3 levels are indeed reduced in muscle tissues and serum of an SMAmouse model. We identified that CTRP3 regulates neuronal protein synthesis including SMN via mTOR pathway. Furthermore, CTRP3 enhances axonal outgrowth and protein synthesis rate, which are well-known impaired processes in SMA motor neurons. Our data revealed a new molecular mechanism by which muscles regulate the physiology of motor neuronsvia secreted molecules. Dysregulation of this mechanism contributes to the pathophysiology of SMA.