Oncotarget

Research Papers:

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

Lucia Gatta, Laura Vitiello, Stefania Gorini, Sergio Chiandotto, Paola Costelli, Anna Maria Giammarioli, Walter Malorni, Giuseppe Rosano and Elisabetta Ferraro _

PDF  |  HTML  |  Supplementary Files  |  How to cite  |  Order a Reprint

Oncotarget. 2017; 8:113938-113956. https://doi.org/10.18632/oncotarget.23044

Metrics: PDF 1238 views  |   HTML 2747 views  |   ?  


Abstract

Lucia Gatta1, Laura Vitiello1, Stefania Gorini1, Sergio Chiandotto2, Paola Costelli3,4, Anna Maria Giammarioli5, Walter Malorni5, Giuseppe Rosano6 and Elisabetta Ferraro1

1Laboratory of Pathophysiology of Cachexia and Metabolism of Skeletal Muscle, IRCCS San Raffaele Pisana, Rome, Italy

2Department of Molecular and Clinical Medicine (DMCM), C/o Department of Surgery “Pietro Valdoni”, Sapienza University of Rome, Rome, Italy

3Department of Clinical and Biological Sciences, University of Turin, Turin, Italy

4Interuniversity Institute of Myology-IIM, Chieti, Italy

5Department of Therapeutic Research and Medicine Evaluation, Istituto Superiore di Sanita, Rome, Italy

6Cardiovascular and Cell Sciences Institute, St George’s University of London, Cranmer Terrace, London, UK

Correspondence to:

Elisabetta Ferraro, email: elisabetta.ferraro@sanraffaele.it

Keywords: metabolism; myogenesis; C26 mice; cachexia; trimetazidine

Received: April 07, 2017    Accepted: November 28, 2017    Published: December 08, 2017

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.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 23044