Resistance training in patients with single, large-scale deletions of mitochondrial DNA

Abstract

Dramatic tissue variation in mitochondrial heteroplasmy has been found to exist in patients with sporadic mitochondrial DNA (mtDNA) mutations. Despite high abundance in mature skeletal muscle, levels of the causative mutation are low or undetectable in satellite cells. The activation of these typically quiescent mitotic cells and subsequent shifting of wild-type mtDNA templates to mature muscle have been proposed as a means of restoring a more normal mitochondrial genotype and function in these patients. Because resistance exercise is known to serve as a stimulus for satellite cell induction within active skeletal muscle, this study sought to assess the therapeutic potential of resistance training in eight patients with single, large-scale mtDNA deletions by assessing: physiological determinants of peak muscle strength and oxidative capacity and muscle biopsy-derived measures of damage, mtDNA mutation load, level of oxidative impairment and satellite cell numbers. Our results show that 12 weeks of progressive overload leg resistance training led to: (i) increased muscle strength; (ii) myofibre damage and regeneration; (iii) increased proportion of neural cell adhesion molecule (NCAM)-positive satellite cells; (iv) improved muscle oxidative capacity. Taken together, we believe these findings support the hypothesis of resistance exercise-induced mitochondrial gene-shifting in muscle containing satellite cells which have low or absent levels of deleted mtDNA. Further investigation is warranted to refine parameters of the exercise training protocol in order to maximize the training effect on mitochondrial genotype and treatment potential for patients with selected, sporadic mutations of mtDNA in skeletal muscle.

Muscle oxidative phosphorylation quantitation using creatine chemical exchange saturation transfer (CrCEST) MRI in mitochondrial disorders

“…This result has a basis in both clinical and epidemiologic observations. Most physicians recommend exercise therapy for individuals with mitochondrial disorders (26), based on evidence of clinical benefit in mitochondrial disease (27,28) and myriad other conditions (29). The optimal exercise therapy for individuals with metabolic myopathy remains the focus of ongoing study.…”

The Pleiotropic Effect of Physical Exercise on Mitochondrial Dynamics in Aging Skeletal Muscle

“…The incorporation of satellite cell-derived mitochondria explains the increase in wild-type mtDNA known as "gene-shifting. " More recently, Murphy and colleagues [139] showed that, in adults with large-scale mtDNA deletions, 12 weeks of RT induced an increase in muscle strength, myofiber damage and regeneration, NCAMpositive and COX-positive satellite cells, and oxidative capacity, supporting the RTe-induced mitochondrial gene-shifting hypothesis. Recently, Spendiff et al [140], in a study on mitochondrial DNA deletion demonstrated that in patients with mitochondrial myopathies, satellite cells presented single, large-scale mtDNA deletion/s at levels comparable with those observed in muscle.…”

Mitochondrial Quality Control as a Therapeutic Target

“…Other NO-based therapeutic approaches to improve skeletal muscle performance involve diet, exercise, and pharmacological agents designed to improve mitochondrial content and OXPHOS efficiency . Aerobic training, a potent stimulus for muscle mitochondrial biogenesis, improves muscle strength and oxidative capacity in patients with mitochondrial myopathy (Murphy et al, 2008) in part through NOdependent mechanisms. An active area of research is to determine the safety, effectiveness, and the most appropriate conditioning regimens for these patients.…”