Modulating the metabolism by trimetazidine enhances myoblast differentiation and promotes myogenesis in cachectic tumor-bearing c26 mice

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.

The Role of Metabolic Remodeling in Macrophage Polarization and Its Effect on Skeletal Muscle Regeneration

“…Therefore, the MFimmunometabolic approach, which does not merely reduce inflammation but also increases M2 activation, might potentially promote muscle regeneration, limiting muscle loss in cachexia. In this regard, we have recently found that the metabolic modulator trimetazidine (TMZ) enhances myogenesis in cancer cachexia in mice (101), along with stimulating M2 reprogramming in vitro (unpublished observations).…”

Muscle mitochondria and oxidative metabolism as targets against cancer cachexia

“…Exercise is also able to activate myogenesis, impinging on satellite cells (SCs) proliferation and differentiation [70] . Accordingly, TMZ treatment modulates the behavior of differentiating murine myoblast, increasing fusion capacity, markers of myogenesis and MyHC levels [71] . These effects are associated with increased expression of metabolic regulators such as PGC-1α and activated AMPK, suggesting an increase in oxidative metabolism [71] .…”

“…Accordingly, TMZ treatment modulates the behavior of differentiating murine myoblast, increasing fusion capacity, markers of myogenesis and MyHC levels [71] . These effects are associated with increased expression of metabolic regulators such as PGC-1α and activated AMPK, suggesting an increase in oxidative metabolism [71] . Similar results have been obtained in isolated murine SCs, in which TMZ increases some markers of differentiation as compared to control [71] .…”

“…These effects are associated with increased expression of metabolic regulators such as PGC-1α and activated AMPK, suggesting an increase in oxidative metabolism [71] . Similar results have been obtained in isolated murine SCs, in which TMZ increases some markers of differentiation as compared to control [71] . Myogenesis is impaired in cachectic animals and cancer patients, likely contributing to muscle wasting [72,73] .…”

“…Myogenesis is impaired in cachectic animals and cancer patients, likely contributing to muscle wasting [72,73] . In this regard, the effect of TMZ on myogenesis markers has been tested on C26-bearing mice, showing increased levels of MyoD and Myogenin [71] . Such results suggest that TMZ could potentially protect against myogenesis impairments.…”