Overexpression of Peroxisome Proliferator-Activated Receptor γ Co-Activator-1α Leads to Muscle Atrophy with Depletion of ATP

Abstract

Peroxisome proliferator-activated receptor-␥ co-activator-1␣ (PGC-1␣) is a key nuclear receptor co-activator for mitochondrial biogenesis. Here we report that overexpression of PGC-1␣ in skeletal muscles increased mitochondrial number and caused atrophy of skeletal muscle, especially type 2B fiber-rich muscles (gastrocnemius, quadriceps, and plantaris). Muscle atrophy became evident at 25 weeks of age, and a portion of the muscle was replaced by adipocytes. Mice showed increased energy expenditure and reduced body weight; thyroid hormone levels were normal. Mitochondria exhibited normal respiratory chain activity per mitochondrion; however, mitochondrial respiration was not inhibited by an ATP synthase inhibitor, oligomycin, clearly indicating that oxidative phosphorylation was uncoupled. Accordingly, ATP content in gastrocnemius was markedly reduced. A similar phenotype is observed in Luft's disease, a mitochondrial disorder that involves increased uncoupling of respiration and muscle atrophy. Our results indicate that overexpression of PGC-1␣ in skeletal muscle increases not only mitochondrial biogenesis but also uncoupling of respiration, resulting in muscle atrophy.

Modest PGC-1α Overexpression in Muscle in Vivo Is Sufficient to Increase Insulin Sensitivity and Palmitate Oxidation in Subsarcolemmal, Not Intermyofibrillar, Mitochondria

“…63). In PGC-1␣ transgenic mice (PGC-1␣ mRNA increased 10 -13-fold), whole body oxygen consumption was increased and AMP concentrations were increased ϳ10-fold (64). It would seem unlikely that the modest PGC-1␣ overexpression in a single muscle in the present study would have elicited such effects on AMP concentrations.…”

PPARγ-coactivator-1α gene transfer reduces neuronal loss and amyloid-β generation by reducing β-secretase in an Alzheimer’s disease model

“…The results of this publication were obtained from a transgenic mouse overexpressing elevated levels of PGC-1α under a promoter not specific for a particular cell type and, consequently, the results do not necessarily have to coincide with our model, in which the gene is expressed for only 4 mo in certain brain areas (27). Indeed, sustained high overexpression of PGC-1α produced toxic effects in muscles and heart, caused or accompanied by extensive mitochondrial proliferation and by myopathy (28,29). Extremely high levels of PGC-1α achieved with adenoviral vectors also resulted in deleterious effects in dopaminergic neurons, in susbtantia nigra (30,31) as opposed to the striatum, where fourfold higher levels were not toxic, in mouse models of Huntington's and Parkinson's diseases (32,33).…”

Fiber Types in Mammalian Skeletal Muscles

“…However, mitochondrial dysfunction leading to ATP depletion and muscle atrophy has also been reported in these muscles (546). No significant difference in fiber type distribution was observed in the soleus muscle from PGC-1␣ knockout mice, but the level of transcripts of mitochondrial ATP synthase and cytochrome oxidase subunits was decreased.…”