Dataset Information

The mitochondrial metabolic reprogramming agent trimetazidine as an 'exercise mimetic' in cachectic C26-bearing mice.

ABSTRACT:

Background

Cancer cachexia is characterized by muscle depletion and exercise intolerance caused by an imbalance between protein synthesis and degradation and by impaired myogenesis. Myofibre metabolic efficiency is crucial so as to assure optimal muscle function. Some drugs are able to reprogram cell metabolism and, in some cases, to enhance metabolic efficiency. Based on these premises, we chose to investigate the ability of the metabolic modulator trimetazidine (TMZ) to counteract skeletal muscle dysfunctions and wasting occurring in cancer cachexia.

Methods

For this purpose, we used mice bearing the C26 colon carcinoma as a model of cancer cachexia. Mice received 5 mg/kg TMZ (i.p.) once a day for 12 consecutive days. A forelimb grip strength test was performed and tibialis anterior, and gastrocnemius muscles were excised for analysis. Ex vivo measurement of skeletal muscle contractile properties was also performed.

Results

Our data showed that TMZ induces some effects typically achieved through exercise, among which is grip strength increase, an enhanced fast-to slow myofibre phenotype shift, reduced glycaemia, PGC1? up-regulation, oxidative metabolism, and mitochondrial biogenesis. TMZ also partially restores the myofibre cross-sectional area in C26-bearing mice, while modulation of autophagy and apoptosis were excluded as mediators of TMZ effects.

Conclusions

In conclusion, our data show that TMZ acts like an 'exercise mimetic' and is able to enhance some mechanisms of adaptation to stress in cancer cachexia. This makes the modulation of the metabolism, and in particular TMZ, a suitable candidate for a therapeutic rehabilitative protocol design, particularly considering that TMZ has already been approved for clinical use.

SUBMITTER: Molinari F

PROVIDER: S-EPMC5700442 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Publications

The mitochondrial metabolic reprogramming agent trimetazidine as an 'exercise mimetic' in cachectic C26-bearing mice.

Molinari Francesca F Pin Fabrizio F Gorini Stefania S Chiandotto Sergio S Pontecorvo Laura L Penna Fabio F Rizzuto Emanuele E Pisu Simona S Musarò Antonio A Costelli Paola P Rosano Giuseppe G Ferraro Elisabetta E

Journal of cachexia, sarcopenia and muscle 20171111 6

<h4>Background</h4>Cancer cachexia is characterized by muscle depletion and exercise intolerance caused by an imbalance between protein synthesis and degradation and by impaired myogenesis. Myofibre metabolic efficiency is crucial so as to assure optimal muscle function. Some drugs are able to reprogram cell metabolism and, in some cases, to enhance metabolic efficiency. Based on these premises, we chose to investigate the ability of the metabolic modulator trimetazidine (TMZ) to counteract skel ...[more]

PMID: 29130633

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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.

Dataset Information

The mitochondrial metabolic reprogramming agent trimetazidine as an 'exercise mimetic' in cachectic C26-bearing mice.

Background

Methods

Results

Conclusions

Publications

The mitochondrial metabolic reprogramming agent trimetazidine as an 'exercise mimetic' in cachectic C26-bearing mice.

Similar Datasets

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