Effects of exercise training on skeletal muscle function in patients with mitochondrial myopathy: a systematic review

Mitochondrial myopathy (MM) is a group of rare, progressive muscle disorders characterized by impaired oxidative phosphorylation due to mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) mutations, leading to exercise intolerance, muscle weakness, and metabolic dysfunction. Although exercise is increasingly recognized for its capacity to enhance mitochondrial function and muscle performance, the specific effects of different exercise prescriptions (in terms of modality, intensity, and duration) on MM and their phenotype-specific outcomes remain heterogeneous. This study systematically investigates how various exercise types influence mitochondrial function, muscle performance, and clinical outcomes across MM subtypes.

Databases including PubMed, Web of Science, Embase, and Scopus were searched from 1990 to September 2025. Clinical trials involving exercise interventions in MM patients were included, with outcomes covering exercise capacity, muscle function, mitochondrial markers, and metabolic indices. Risk of bias was assessed using Revised Cochrane Risk-of-Bias Tool for Randomized Trials (RoB 2) and Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I V2), and methodological quality was appraised with the Mixed Methods Appraisal Tool (MMAT).

Fifteen studies (1 randomized controlled trial and 14 non-randomized trials) including a total of 157 MM patients (sample size per study: 4-20) were analyzed. Moderate-intensity aerobic and resistance exercise consistently improved maximal oxygen uptake (VO₂ max), maximal workload (W max), muscle strength, and mitochondrial enzyme activity, with no consistent group-level increases observed in creatine kinase (CK) levels or mtDNA mutation burden. Aerobic training enhanced oxidative capacity, phosphocreatine (PCr) recovery, and antioxidant defense, while resistance training improved muscle strength, satellite cell activation, and reduced cytochrome c oxidase (COX)-deficient fibers. Combined regimens yielded additive benefits. Most interventions lasted 8-14 weeks, 3-5 sessions per week. Phenotype-specific responses were evident: patients with large-scale deletions or m.3243A>G mutations showed favorable adaptation, whereas other point mutations or microdeletions displayed variable or adverse responses.

Moderate-intensity, phenotype-specific exercise prescriptions, especially those integrating both aerobic and resistance components, may enhance mitochondrial and muscular function in patients with mitochondrial myopathy while reducing the likelihood of adverse effects. However, larger controlled trials are needed to confirm long-term efficacy and to clarify potential risk profiles.

https://www.crd.york.ac.uk/PROSPERO/view/CRD420251145502, PROSPERO CRD420251145502.