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 Ca 2+-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 Ca 2+-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 ofnecrosis, 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