Dysregulated autophagy in muscle precursor cells from humans with type 2 diabetes

Abstract

Autophagy is active during cellular remodeling including muscle differentiation. Muscle differentiation is dysregulated in type 2 diabetes and we therefore hypothesize that muscle precursor cells from people with type 2 diabetes (T2DM) have a dysregulation of their autophagy leading to impaired myogenesis. Muscle precursor cells were isolated from people with T2DM or healthy controls and differentiated in vitro. Autophagy marker levels were assessed by immunoblotting. Differentially expressed autophagy-related genes between healthy and T2DM groups were identified based on a previously published RNA-sequencing data-set, which we verified by RT-qPCR. siRNA was used to assess the function of differentially expressed autophagy genes. Basal autophagy increases during human muscle differentiation, while T2DM muscle cells have reduced levels of autophagy marker ATG7 and show a blunted response to starvation. Moreover, we demonstrate that the 3 non-canonical autophagy genes DRAM1, VAMP8 and TP53INP1 as differentially expressed between healthy and T2DM groups during myoblast differentiation, and that T53INP1 knock-down alters expression of both pro-and anti-apoptotic genes. In vitro differentiated T2DM muscle cells show differential expression of autophagy-related genes. These genes do not regulate myogenic transcription factors but may rather be involved in p53-associated myoblast apoptosis during early myogenesis.