High-intensity interval training in the form of isometric contraction improves fatigue resistance in dystrophin-deficient muscle.

Duchenne muscular dystrophy (DMD) is a genetic muscle-wasting disorder characterised by progressive muscle weakness and easy fatigability. Here we examined whether high-intensity interval training (HIIT) in the form of isometric contraction improves fatigue resistance in skeletal muscle from dystrophin-deficient mdx52 mice. Isometric HIIT was performed on plantar flexor muscles in vivo with supramaximal electrical stimulation every other day for 4 weeks (a total of 15 sessions). In the non-trained contralateral gastrocnemius muscle from mdx52 mice, the decreased fatigue resistance was associated with a reduction in the amount of PGC-1α, citrate synthase activity, mitochondrial respiratory complex II, LC3B-II/I ratio, and mitophagy-related gene expression (i.e., Pink1, parkin, Bnip3, and Bcl2l13) as well as an increase in the phosphorylation levels of Src Tyr416 and Akt Ser473, the amount of p62, and the percentage of Evans blue dye-positive area. Isometric HIIT restored all these alterations and markedly improved fatigue resistance in mdx52 muscles. Moreover, an acute bout of HIIT increased the phosphorylation levels of AMPK Thr172, ACC Ser79, Ulk1 Ser555, and Drp1 Ser616 in mdx52 muscles. Thus, our data show that HIIT with isometric contractions significantly mitigates histological signs of pathology and improves fatigue resistance in dystrophin-deficient muscles. These beneficial effects can be explained by the restoration of mitochondrial function via AMPK-dependent induction of the mitophagy program and de novo mitochondria biogenesis. KEY POINTS: Skeletal muscle fatigue is often associated with Duchenne muscular dystrophy (DMD) and leads to an inability to perform daily tasks, profoundly decreasing quality of life. We examined the effect of high-intensity interval training (HIIT) in the form of isometric contraction on fatigue resistance in skeletal muscle from the mdx52 mouse model of DMD. Isometric HIIT counteracted the reduced fatigue resistance as well as dystrophic changes in skeletal muscle of mdx52 mice. This beneficial effect could be explained by the restoration of mitochondrial function via AMPK-dependent mitochondrial biogenesis and the induction of mitophagy program in the dystrophic muscles. Abstract figure legend As a result of the loss of dystrophin, increased production of NADPH oxidase 2 (NOX2)- and mitochondria-derived reactive oxygen species (ROS) causes mitochondrial Ca 2+ overload as well as an activation of Src/Akt pathway. This then leads to mitochondrial dysfunction and perturbation of mitophagy, which contribute to dystrophic pathology and decreased fatigue resistance due to accumulation of damaged mitochondria in dystrophin-deficient muscle. High-intensity interval training (HIIT) with isometric contractions mitigates dystrophic alterations and improves fatigue resistance, presumably via AMPK-dependent mitochondrial turnover; dysfunctional mitochondria are eliminated via mitophagy and replaced through de novo mitochondria biogenesis. This article is protected by copyright. All rights reserved.