Peroxisome proliferator-activated receptor γ coactivator1- gene α transfer restores mitochondrial biomass and improves mitochondrial calcium handling in post-necrotic mdx mouse skeletal muscle.
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 Ca(2+)(.) This was associated with reductions in the activity levels of the Ca(2+)-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.
Department of Kinesiology, Faculty of Pharmacy, Université de Montréal, PO Box 6128, Succursalle Centre Ville, Montreal, Quebec, Canada.
Richard
R
Godin
Frederic
F
Daussin
Stefan
S
Matecki
Tong
T
Li
Basil J
BJ
Petrof
Yan
Y
Burelle
D000818:Animals; D002118:Calcium / Q000502:physiology*; D004195:Disease Models, Animal; D016189:Dystrophin / Q000172:deficiency; D018014:Gene Transfer Techniques; D006861:Hydrogen Peroxide / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000473:pathology / Q000502:physiology*; D018482:Muscle, Skeletal / Q000473:pathology / Q000502:physiology*; D020388:Muscular Dystrophy, Duchenne; D009336:Necrosis / Q000473:pathology / Q000503:physiopathology; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D015534:Trans-Activators / Q000502:physiology*; D014157:Transcription Factors
D016189:Dystrophin; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D006861:Hydrogen Peroxide; D002118:Calcium