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

Abstract

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.

Sodium nitrate co-supplementation does not exacerbate low dose metronomic doxorubicin-induced cachexia in healthy mice

“…type IIb) to fast oxidative glycolytic (type IIa) phenotype 73 , we have also demonstrated a reduction in the CSA of glycolytic fibres. These adaptations could be of benefit to skeletal muscles long term, particularly in mitigating the contractile dysfunction and higher fatiguability reported by others in mice 17,27 and humans 74 following chemotherapy administration.…”

“…n = 6-7. www.nature.com/scientificreports/ is dose dependent 44 since other studies that utilized a higher cumulative dose of DOX (i.e. 20-30 mg/kg) have demonstrated significant skeletal muscle wasting [17][18][19][20] . Despite the lack of evidence for skeletal muscle wasting/ atrophy in this model, it is still of interest that our model of LDM DOX administration (12 mg/kg; total cumulative dose over 7 days) can have a substantial acute effect on body and lean (visceral) mass i.e.…”

“…In this study, LDM DOX administration reduced voluntary wheel activity and energy expenditure in a synergistic manner, which was not alleviated by SN co-supplementation. DOX has previously been shown to impair skeletal muscle function and wheel running performance in mice, and this has been associated with mitochondrial dysfunction resulting from changes to the redox status of skeletal muscle 17,20,29,61,62 . In our study, DOX-induced "fatigue" was associated with a molecular marker of increased nitrosative stress (i.e.…”

“…DOX-induced skeletal muscle toxicity is widely accepted to be a consequence of its metabolism at Complex I of the mitochondrial ETC, resulting in mitochondrial dysfunction secondary to the enhancement of oxidative stress. As a consequence, DOX treatment is associated with skeletal muscle atrophy/wasting, as well as functional deficits [17][18][19][20][21][22][23][24][25] as characterized by reduced force production and increased susceptibility to skeletal muscle fatigue in pre-clinical animal models [26][27][28][29] . These data are consistent with clinical descriptions of exercise intolerance, a lesser capacity for activities of daily living and reduced quality of life in patients following chemotherapy treatment [30][31][32] .…”

Protective effects of endurance exercise on skeletal muscle remodeling against doxorubicin-induced myotoxicity in mice

“…It is correctly outlined for the autophagy signaling pathways involved in the health benefits of the skeletal muscle during exercise 38 . Although previous studies applied EXE preconditioning as a counteracting strategy against DOX-mediated myotoxicity and dysfunctions [18][19][20][39][40][41][42][43][44][45][46] , the skeletal muscle regeneration capacity with chronic chemotherapeutic DOX treatment and post-conditioning of EXE training is yet to be examined.…”