Dynamic changes in copper homeostasis and post-transcriptional regulation ofAtp7aduring myogenic differentiation

Abstract

Copper (Cu) is an essential metal required for activity of a number of redox active enzymes that participate in critical cellular pathways such as metabolism and cell signaling.

MTF1, a classic metal sensing transcription factor, promotes myogenesis in response to copper

“…During myogenesis, the cellular levels of Cu increased, which is consistent with a high demand for Cu for proper function of mature tissue [36]. These changes in Cu levels are dependent on the dynamic expression of the Cu + -transporters and the post-transcriptional regulation of Atp7a [36]. However, the mechanisms by which Cu elicits a differentiation effect are unknown.…”

“…In order to induce myogenesis in cultured myoblasts, growth factors are depleted by serum starvation and insulin is added [93,94]. Depletion of insulin from the differentiation medium partially prevents myogenic differentiation, a phenotype that we have recently shown can be rescued by the addition of non-toxic (30 µM) concentrations of CuSO 4 [36].…”

“…Moreover, depletion of Cu from the culture medium inhibits differentiation, which suggests that Cu plays a role in differentiation [36]. However, the molecular mechanisms by which Cu affects differentiation are largely unknown.…”

“…We recently demonstrated that copper is required for the proliferation and differentiation of primary myoblasts derived from mouse satellite cells, which are adult stem cells responsible for skeletal muscle growth and repair from injury [36]. During myogenesis, the cellular levels of Cu increased, which is consistent with a high demand for Cu for proper function of mature tissue [36]. These changes in Cu levels are dependent on the dynamic expression of the Cu + -transporters and the post-transcriptional regulation of Atp7a [36].…”

“…Here, we hypothesized that Cu may have a fundamental role in the regulation of gene expression that drives the differentiation of the skeletal muscle. Activation of the myogenic program at the transcriptional level requires a series of signals, including growth factors, TFs, kinases, chromatin remodelers, histone modifiers, and metal ions [36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52]. Emerging evidence suggests that Cu and potential Cu + -binding TFs play significant roles in mammalian development [53][54][55][56].…”