Peroxisome proliferator‐activated receptor γ coactivator 1‐α gene transfer restores mitochondrial biomass and improves mitochondrial calcium handling in post‐necrotic <i>mdx</i> mouse skeletal muscle

Key points Mitochondria are increasingly implicated in the pathogenesis of Duchenne muscular dystrophy (DMD). However, the extent to which the multiple facets of mitochondrial function are altered remains uncertain due to the lack of detailed assessment. Peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha (PGC1α) was recently shown to improve muscle pathology in dystrophic muscle. However, the mechanisms are not fully elucidated. This study provides novel information on mitochondrial dysfunction in DMD namely that (i) loss of mitochondrial biomass precedes overt respiratory abnormalities, (ii) mitochondrial H2O2 metabolism is improved at a time when no oxidative damage is detectable in the muscle, and (iii) susceptibility to permeability transition pore (PTP) opening is increased, which has only been inferred in the past, but never actually measured. This study also provides new mechanistic information regarding the beneficial effects of PGC1α overexpression upon dystrophic muscles, namely that PGC1α not only increases mitochondrial biomass but also reduces PTP opening, improves mitochondrial Ca2+ handling and reduces the activation of Ca2+ and mitochondria‐dependent proteases in muscles of mdx mice. These mechanisms were not examined in previous investigations, which had largely attributed the improved histopathology after PGC1α therapy to utrophin upregulation. Abstract Alterations of mitochondrial function have been implicated in the pathogenesis of Duchenne muscular dystrophy. In the present study, mitochondrial respiratory function, reactive oxygen species (ROS) dynamics and susceptibility to Ca2+‐induced permeability transition pore (PTP) opening were investigated in permeabilized skeletal muscle fibres of 6‐week‐old mdx mice, in order to characterize the magnitude and nature of mitochondrial dysfunction at an early post‐necrotic stage of the disease. Short‐term overexpression of the transcriptional co‐activator PGC1α, achieved by in vivo plasmid transfection, was then performed to determine whether this intervention could prevent mitochondrial impairment and mitigate associated biochemical abnormalities. Compared with normal mice, mdx mice exhibited a lower mitochondrial biomass and oxidative capacity, greater ROS buffering capabilities, and an increased vulnerability to Ca2+‐induced opening of the mitochondrial permeability transition pore complex. PGC1α gene transfer restored mitochondrial biomass, normalized the susceptibility to PTP opening and increased the capacity of mitochondria to buffer Ca2+. This was associated with reductions in the activity levels of the Ca2+‐dependent protease calpain as well as caspases 3 and 9. Overall, these results suggest that overexpression of PGC1α in dystrophin‐deficient muscles, after the onset of necrosis, has direct beneficial effects upon multiple aspects of mitochondrial function, which may in turn mitigate the activation of proteolytic and apoptotic signalling pathways associated with disease progression.

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