Bmi1 enhances skeletal muscle regeneration through MT1-mediated oxidative stress protection in a mouse model of dystrophinopathy

Abstract

The Polycomb group (PcG) protein Bmi1 is an essential epigenetic regulator of stem cell function during normal development and in adult organ systems. We show that mild upregulation of Bmi1 expression in the adult stem cells of the skeletal muscle leads to a remarkable improvement of muscle function in a mouse model of Duchenne muscular dystrophy. The molecular mechanism underlying enhanced physiological function of Bmi1 depends on the injury context and it is mediated by metallothionein 1 (MT1)-driven modulation of resistance to oxidative stress in the satellite cell population. These results lay the basis for developing Bmi1 pharmacological activators, which either alone or in combination with MT1 agonists could be a powerful novel therapeutic approach to improve regeneration in muscle wasting conditions.

Invited Review: Polycomb group genes in the regeneration of the healthy and pathological skeletal muscle

“…Our group has shown that Bmi1 overexpression in the satellite cells increases the Pax7 + /MyoD − proportion of the satellite cells in vitro , without impairing their differentiation potential . We also showed that mild overexpression of Bmi1 specifically in the satellite cells enhances the muscle strength of mdx mice after challenge with treadmill exercise for 6 weeks (Figure ).…”

“…Our group has shown that Bmi1 overexpression in the satellite cells increases the Pax7 + /MyoD − proportion of the satellite cells in vitro , without impairing their differentiation potential . We also showed that mild overexpression of Bmi1 specifically in the satellite cells enhances the muscle strength of mdx mice after challenge with treadmill exercise for 6 weeks (Figure ). Importantly, a similar experimental approach did not lead to a significant improvement of muscle strength in non‐dystrophic mice upon acute traumatic muscle injury, highlighting the context‐specificity of the efficacy of Bmi1 modulation in muscle regeneration.…”

“…The role of PcG proteins during muscle regeneration has been recently studied in mouse models. Bmi1 expression in particular is upregulated in satellite cells during the first phases of muscle regeneration and ablation of Bmi1 leads to an increased proportion of committed myogenic precursor cells. In keeping with a depletion of satellite cell pool, when the muscle is challenged with repeated injuries, Bmi1 −/− mice display a compromised and delayed regeneration with defects in the maturation of the regenerating fibres (Figure ).…”

“…In the mdx mouse, Bmi1 is downregulated in the satellite cells . In vivo , mdx;Bmi1 −/− show fewer and smaller centrally nucleated fibres in the diaphragm , a muscle known to be particularly affected by chronic muscle wasting and repeated cycles of repair due to its essential role in respiration.…”

“…Interestingly, the molecular mechanism mediating Bmi1 function in satellite cells is different in the context of Bmi1 depletion and overexpression. In satellite cells derived from mdx;Bmi1 −/− the phenotype is dependent on the activation of the Ink4a/Arf locus; in the overexpression context a Metallothionein 1‐mediated protection from oxidative stress‐induced cellular damage is instead responsible for the amelioration of the performance of the dystrophic muscles under a forced exercise regime (Figure ).…”