Abstract
Purpose: Mitochondrial diseases (MD) are among the most prevalent neuromuscular disorders. Unfortunately, no curative treatment is yet available. This study analyzed the effects of exercise training in an animal model of respiratory chain complex I deficiency, the Harlequin (Hq) mouse, which replicates the clinical features of this condition.Methods: Male heterozygous Harlequin (Hq/Y) mice were assigned to an “exercise” (n = 10) or a “sedentary” control group (n = 11), with the former being submitted to an 8 week combined exercise training intervention (aerobic + resistance training performed five times/week). Aerobic fitness, grip strength, and balance were assessed at the beginning and at the end of the intervention period in all the Hq mice. Muscle biochemical analyses (with results expressed as percentage of reference data from age/sex-matched sedentary wild-type mice [n = 12]) were performed at the end of the aforementioned period for the assessment of major molecular signaling pathways involved in muscle anabolism (mTOR activation) and mitochondrial biogenesis (proliferator activated receptor gamma co-activator 1α [PGC-1α] levels), and enzyme activity and levels of respiratory chain complexes, and antioxidant enzyme levels.Results: Exercise training resulted in significant improvements in aerobic fitness (−33 ± 13 m and 83 ± 43 m for the difference post- vs. pre-intervention in total distance covered in the treadmill tests in control and exercise group, respectively, p = 0.014) and muscle strength (2 ± 4 g vs. 17 ± 6 g for the difference post vs. pre-intervention, p = 0.037) compared to the control group. Higher levels of ribosomal protein S6 kinase beta-1 phosphorylated at threonine 389 (156 ± 30% vs. 249 ± 30%, p = 0.028) and PGC-1α (82 ± 7% vs. 126 ± 19% p = 0.032) were observed in the exercise-trained mice compared with the control group. A higher activity of respiratory chain complexes I (75 ± 4% vs. 95 ± 6%, p = 0.019), III (79 ± 5% vs. 97 ± 4%, p = 0.031), and V (77 ± 9% vs. 105 ± 9%, p = 0.024) was also found with exercise training. Exercised mice presented with lower catalase levels (204 ± 22% vs. 141 ± 23%, p = 0.036).Conclusion: In a mouse model of MD, a training intervention combining aerobic and resistance exercise increased aerobic fitness and muscle strength, and mild improvements were found for activated signaling pathways involved in muscle mitochondrial biogenesis and anabolism, OXPHOS complex activity, and redox status in muscle tissue.
Highlights
Mitochondrial diseases (MD) encompass a heterogeneous group of rare diseases caused by defects in oxidative phosphorylation (OXPHOS) [1, 2], and are among the most common neuromuscular disorders, but showing variable estimated prevalence [3,4,5]
Exercise training resulted in significant improvements in aerobic fitness (−33 ± 13 m and 83 ± 43 m for the difference post- vs. pre-intervention in total distance covered in the treadmill tests in control and exercise group, respectively, p = 0.014) and muscle strength (2 ± 4 g vs. 17 ± 6 g for the difference post vs. pre-intervention, p = 0.037) compared to the control group
Higher levels of ribosomal protein S6 kinase beta-1 phosphorylated at threonine 389 (156 ± 30% vs. 249 ± 30%, p = 0.028) and proliferatoractivated receptor-gamma co-activator 1α (PGC-1α) (82 ± 7% vs. 126 ± 19% p = 0.032) were observed in the exercise-trained mice compared with the control group
Summary
Mitochondrial diseases (MD) encompass a heterogeneous group of rare diseases caused by defects in oxidative phosphorylation (OXPHOS) [1, 2], and are among the most common neuromuscular disorders, but showing variable estimated prevalence [3,4,5]. No curative treatment is yet available for MD, preclinical evidence from animal and in vitro studies suggests that promoting the increase in mitochondrial content or mitochondrial biogenesis, through the activation of peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC-1α) might be a therapeutic option [8, 9] In this respect, regular endurance exercise is known to be a potent stimulus for muscle mitochondrial biogenesis [10], and previous research has shown that endurance-based exercise interventions can increase the muscle oxidative capacity of patients with MD, as directly reflected by increases in the activity of citrate synthase (CS) and respiratory chain complexes in skeletal muscle biopsies [11,12,13], or indirectly, by improvements in patients’ aerobic fitness [11,12,13,14,15,16,17,18]. We recently described significant improvements in upper-, lower-body, and respiratory muscle strength in 12 well-characterized MD patients (all with genetic diagnosis) after 8 weeks of combined resistance, endurance and respiratory training [14]
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