Aerobic exercise, but not metformin, prevents reduction of muscular performance by AMPk activation in mice on doxorubicin chemotherapy

Doxorubicin (DOX) is a chemotherapy agent widely used in clinical practice, and it is very efficient in tumor suppression, but the use of DOX is limited by a strong association with the development of severe muscle atrophy and cardiotoxicity effects. Reversion or neutralization of the muscular atrop...

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Bibliographic Details
Published in:Journal of cellular physiology 2018-12, Vol.233 (12), p.9652-9662
Main Authors: Lima, Edson A., Sousa, Luís G. O., Teixeira, Alexandre Abilio, Marshall, Andrea G., Zanchi, Nelo E., Neto, José C. Rosa
Format: Article
Language:English
Subjects:
Activation
Aerobic capacity
aerobic exercise
Aerobics
AMP
Antidiabetics
Atrophy
Bioenergetics
Body weight
Cardiotoxicity
Chemotherapy
Doxorubicin
doxorubicin (DOX)
Exercise
Fatigue
Kinases
Metabolism
Metformin
metformin (MET)
Mice
muscle wasting
Muscles
Muscular fatigue
Musculoskeletal system
Neutralization
Physical exercise
Physical fitness
Protein biosynthesis
Protein kinase
Protein synthesis
Proteins
Reversion
Side effects
Skeletal muscle
Tumor suppression
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Summary:Doxorubicin (DOX) is a chemotherapy agent widely used in clinical practice, and it is very efficient in tumor suppression, but the use of DOX is limited by a strong association with the development of severe muscle atrophy and cardiotoxicity effects. Reversion or neutralization of the muscular atrophy can lead to a better prognosis. Recent studies have proposed that the negative effect of DOX on skeletal muscle is linked to its inhibition of AMP‐activated protein kinase (AMPk), a key mediator of cellular metabolism. On the basis of this, our goal was to evaluate if aerobic exercise or metformin treatment, activators of AMPk, would be able to attenuate the deleterious effects on skeletal muscle induced by the DOX treatment. C57BL6 mice received either saline (control) or DOX (2.5 mg/kg body weight) intraperitoneally, twice a week. The animals on DOX were further divided into groups that received adjuvant treatment in the form of moderate aerobic physical exercise (DOX+T) or metformin gavage (300 mg/body weight/day). Body weight, metabolism, distance run, muscle fiber cross‐sectional area (CSA), and protein synthesis and degradation were assessed. We demonstrated that aerobic training, but not metformin, associated with DOX increased the maximal aerobic capacity without changing muscle mass or fiber CSA, rescuing the muscle fatigue observed with DOX treatment alone. This improvement was associated with AMPk activation, thus surpassing the negative effects of DOX on muscle performance and bioenergetics. In conclusion, aerobic exercise increases AMPk activation and improved the skeletal muscle function, reducing the side effects of DOX. Pharmacological and nonpharmacological adjuvant strategies in chemotherapy treatment are presented. Decreased muscle performance caused by chemotherapeutic treatment can be recovered with aerobic exercise. Aerobic training is able to bring important benefits to counteract doxorubicin metabolic effects in the whole body and skeletal muscle.
ISSN:0021-9541
1097-4652
DOI:10.1002/jcp.26880