Abstract
Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder, which causes dysfunction/loss of lower motor neurons and muscle weakness as well as atrophy. While SMA is 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 SMA muscle secretome and confirmed that CTRP3 levels are indeed reduced in muscle tissues and serum of an SMA mouse 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 neurons via secreted molecules. Dysregulation of this mechanism contributes to the pathophysiology of SMA.
Highlights
Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder with an incidence of 1 per 6000–10, 000 newborns [66, 72]
Systemic muscle secretome analysis: secretion of C1q/TNF-related protein 3 (CTRP3) is reduced in survival motor neuron (SMN)-deficient muscle cells We screened secreted proteins from control and SMNdeficient muscle cells with a combination of two metabolic labeling methods and mass spectrometry (MS)
While we cannot fully explain the mechanism at the moment, we found that the ratio of protein synthesis between soma and axons is reduced in SMA motor neurons compared to WT ones, and that this is enhanced by CTRP3 treatment (Fig. 6 h and i)
Summary
Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder with an incidence of 1 per 6000–10, 000 newborns [66, 72]. While the severity of SMA varies, characteristic phenotypes of SMA patients include muscle weakness and atrophy, defects in neuromuscular junctions (NMJs) and motor neuron loss. In more than 95% of cases, SMA is caused by loss or mutations of the SMN1 (Survival of Motor Neuron 1) gene. In the milder cases of SMA, with 3–6 copies of SMN2, are pathological symptoms restricted to motor neurons, NMJs and muscles [75].
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