Mutations in SIL1, a nucleotide exchange factor for the endoplasmic reticulum (ER) Hsp70 ortholog, BiP, cause Marinesco-Sjögren syndrome (MSS), an autosomal recessive disorder affecting multiple systems. Using a MSS mouse model, we characterized the molecular aspects of the progressive myopathy associated with MSS. Proteomic profiling of quadriceps, at the onset of myopathy, revealed that loss of Sil1 affected multiple pathways critical to muscle physiology. We observed an increase in a subset of ER chaperones prior to the onset of muscle weakness, which was complemented by an up-regulation of multiple protein degradation pathway components. Nonetheless, these compensatory responses were insufficient to maintain normal expression of secretory pathway proteins, including Insulin and IGF-1 receptor levels. Despite decreased levels of these receptor tyrosine kinases in skeletal muscles, there was a basal enhancement of downstream PI3K-Akt signaling, Glut4 glucose transporter levels, and glucose uptake. However, these counter-measures were insufficient to prevent glucose intolerance and insulin resistance. Together, these data reveal defects in maintaining ER homeostasis upon Sil1 loss, which are countered by multiple compensatory actions that are ultimately unsuccessful, leading to proteostasis collapse and myopathy.

Sil1, the ER Hsp70 co-chaperone, plays a critical role in maintaining skeletal muscle proteostasis and physiology

255th National Meeting (2018)

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