Abstract
Trimetazidine (TMZ) is a metabolic reprogramming agent able to partially inhibit mitochondrial free fatty acid β-oxidation while enhancing glucose oxidation. Here we have found that the metabolic shift driven by TMZ enhances the myogenic potential of skeletal muscle progenitor cells leading to MyoD, Myogenin, Desmin and the slow isoforms of troponin C and I over-expression. Moreover, similarly to exercise, TMZ stimulates the phosphorylation of the AMP-activated protein kinase (AMPK) and up-regulates the peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC1α), both of which are known to enhance the mitochondrial biogenesis necessary for myoblast differentiation. TMZ also induces autophagy which is required during myoblast differentiation and promotes myoblast alignment which allows cell fusion and myofiber formation. Finally, we found that intraperitoneally administered TMZ (5mg/kg) is able to stimulate myogenesis in vivo both in a mice model of cancer cachexia (C26 mice) and upon cardiotoxin damage. Collectively, our work demonstrates that TMZ enhances myoblast differentiation and promotes myogenesis, which might contribute recovering stem cell blunted regenerative capacity and counteracting muscle wasting, thanks to the formation of new myofibers; TMZ is already in use in humans as an anti-anginal drug and its repositioning might impact significantly on aging and regeneration-impaired disorders, including cancer cachexia, as well as have implications in regenerative medicine.
Highlights
The adult myogenic response plays a key a role in the maintenance of skeletal muscle homeostasis
In order to explore the effect of metabolic modulation on skeletal myoblast differentiation, we induced C2C12 myoblasts to differentiate by culturing them on differentiation medium (DM) in presence or absence of various concentrations of TMZ (1-5-30 μM)
This is consistent with the knowledge that the differentiation of myoblasts is associated with a metabolic shift from a predominantly glycolytic state to a metabolism www.impactjournals.com/oncotarget based mainly on mitochondrial oxidative phosphorylation; this shift is thought to be needed to support the higher energetic demand of contractile muscle [52]
Summary
The adult myogenic response plays a key a role in the maintenance of skeletal muscle homeostasis. Adult myogenesis is triggered by skeletal muscle injuries which lead to induction of new myofiber regeneration mainly sustained by resident myogenic satellite cells (SCs), located underneath the basal lamina of myofibers www.impactjournals.com/oncotarget [1,2,3]. SCs become activated and differentiate into proliferating myoblasts expressing typical myogenic markers such as Desmin, Myf-5 and MyoD [4, 5]. Recent data show that the defects in regeneration are due to a reduced amount of SCs and to their impaired functionality and myogenic capacity, which have been associated, among the other causes, with alterations in apoptosis, autophagy and reduced activation of specific signaling pathways [18,19,20,21,22,23, 24,25,26,27]. It has been proposed that, in order to maintain their energy levels and survive in nutrient poor conditions, SCs rely on autophagy and that during the transition from quiescence to activation, sirtuin 1 (SIRT1) is required for autophagy induction in order to meet bioenergetic demands [28]
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