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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 ?-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-? (PGC1?), 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.

SUBMITTER: Gatta L

PROVIDER: S-EPMC5768376 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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

Gatta Lucia L Vitiello Laura L Gorini Stefania S Chiandotto Sergio S Costelli Paola P Giammarioli Anna Maria AM Malorni Walter W Rosano Giuseppe G Ferraro Elisabetta E

Oncotarget 20171208 69

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-regul ...[more]

PMID: 29371959

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Project description:Targeted exercise combined with nutritional and pharmacological strategies is commonly considered to be the most optimal strategy to reduce the development and progression of cachexia. For COPD patients, this multi-targeted treatment has shown beneficial effects. However, in many, physical activity is seriously hampered by frailty and fatigue. In the present study, effects of whole-body-vibration-training (WBV) were investigated, as potential alternative to active exercise, on body mass, muscle mass and function in tumour bearing mice. Twenty-four male CD2F1-mice (6-8 weeks, 21.5 ± 0.2 g) were stratified into four groups: control, control + WBV, C26 tumour-bearing, and C26 tumour-bearing + WBV. From day 1, whole-body-vibration was daily performed for 19 days (15 min, 45 Hz, 1.0 g acceleration). General outcome measures included body mass and composition, daily activity, blood analysis, assessments of muscle histology, function, and whole genome gene expression in m. soleus (SOL), m. extensor digitorum longus (EDL), and heart. Body mass, lean and fat mass and EDL mass were all lower in tumour bearing mice compared to controls. Except from improved contractility in SOL, no effects of vibration training were found on cachexia related general outcomes in control or tumour groups, as PCA analysis did not result in a distinction between corresponding groups. However, analysis of transcriptome data clearly revealed a distinction between tumour and trained tumour groups. WBV reduced the tumour-related effects on muscle gene expression in EDL, SOL and heart. Gene Set Enrichment Analysis showed that these effects were associated with attenuation of the upregulation of the proteasome pathway in SOL. These data suggest that WBV had minor effects on cachexia related general outcomes in the present experimental set-up, while muscle transcriptome showed changes associated with positive effects. This calls for follow-up studies applying longer treatment periods of WBV as component of a multiple-target intervention.

Project description:BackgroundTyrosine kinase inhibitors (TKIs) are effective therapies with demonstrated antineoplastic activity. Nilotinib is a second-generation FDA-approved TKI designed to overcome Imatinib resistance and intolerance in patients with chronic myelogenous leukemia (CML). Interestingly, TKIs have also been shown to be an efficient treatment for several non-malignant disorders such fibrotic diseases, including those affecting skeletal muscles.MethodsWe investigated the role of Nilotinib on skeletal myogenesis using the well-established C2C12 myoblast cell line. We evaluated the impact of Nilotinib during the time course of skeletal myogenesis. We compared the effect of Nilotinib with the well-known p38 MAPK inhibitor SB203580. MEK1/2 UO126 and PI3K/AKT LY294002 inhibitors were used to identify the signaling pathways involved in Nilotinib-related effects on myoblast. Adult primary myoblasts were also used to corroborate the inhibition of myoblasts fusion and myotube-nuclei positioning by Nilotinib.ResultsWe found that Nilotinib inhibited myogenic differentiation, reducing the number of myogenin-positive myoblasts and decreasing myogenin and MyoD expression. Furthermore, Nilotinib-mediated anti-myogenic effects impair myotube formation, myosin heavy chain expression, and compromise myotube-nuclei positioning. In addition, we found that p38 MAPK is a new off-target protein of Nilotinib, which causes inhibition of p38 phosphorylation in a similar manner as the well-characterized p38 inhibitor SB203580. Nilotinib induces the activation of ERK1/2 and AKT on myoblasts but not in myotubes. We also found that Nilotinib stimulates myoblast proliferation, a process dependent on ERK1/2 and AKT activation.ConclusionsOur findings suggest that Nilotinib may have important negative effects on muscle homeostasis, inhibiting myogenic differentiation but stimulating myoblasts proliferation. Additionally, we found that Nilotinib stimulates the activation of ERK1/2 and AKT. On the other hand, we suggest that p38 MAPK is a new off-target of Nilotinib. Thus, there is a necessity for future studies to investigate the long-term effects of TKIs on skeletal muscle homeostasis, along with potential detrimental effects in cell differentiation and proliferation in patients receiving TKI therapies.

Dataset Information

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

Publications

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

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