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

Gatta, L; Vitiello, L; Gorini, S; Chiandotto, S; Costelli, P; Giammarioli, AM; Malorni, W; Rosano, G; Ferraro, E (2017) Modulating the metabolism by trimetazidine enhances myoblast differentiation and promotes myogenesis in cachectic tumor-bearing c26 mice. Oncotarget, 8 (69). pp. 113938-113956. ISSN 1949-2553 https://doi.org/10.18632/oncotarget.23044
SGUL Authors: Rosano, Giuseppe Massimo Claudio

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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.

Item Type: Article
Additional Information: Copyright: Gatta et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Keywords: C26 mice, cachexia, metabolism, myogenesis, trimetazidine
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Journal or Publication Title: Oncotarget
ISSN: 1949-2553
Language: eng
Dates:
DateEvent
26 December 2017Published
8 December 2017Published Online
28 November 2017Accepted
Publisher License: Creative Commons: Attribution 3.0
Projects:
Project IDFunderFunder ID
Ricerca Finalizzata-RF-2010-2318508Italian Ministry of Health for Institutional ResearchUNSPECIFIED
PubMed ID: 29371959
Go to PubMed abstract
URI: http://sgultest.da.ulcc.ac.uk/id/eprint/111205
Publisher's version: https://doi.org/10.18632/oncotarget.23044

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