In previous studies, we characterized a new hormonal pathway involving a 
mitochondrial T3 receptor (p43) acting as a mitochondrial transcription factor. 
In in vitro and in vivo studies, we have shown that p43 increases mitochondrial 
transcription and mitochondrial biogenesis. In addition, p43 overexpression in 
skeletal muscle stimulates mitochondrial respiration and induces a shift in 
metabolic and contractile features of muscle fibers which became more 
oxidative.Here we have studied the influence of p43 overexpression in skeletal 
muscle of mice during aging. We report that p43 overexpression initially 
increased mitochondrial mass. However, after the early rise in mitochondrial DNA 
occurring at 2 months of age in transgenic mice, we observed a progressive 
decrease of mitochondrial DNA content which became 2-fold lower at 23 months of 
age relatively to control animals. Moreover, p43 overexpression induced an 
oxidative stress characterized by a strong increase of lipid peroxidation and 
protein oxidation in quadriceps muscle, although antioxidant enzyme activities 
(catalase and superoxide dismutase) were stimulated. In addition, muscle atrophy 
became detectable at 6 months of age, probably through a stimulation of the 
ubiquitin proteasome pathway via two muscle-specific ubiquitin ligases E3, 
Atrogin-1/MAFbx and MuRF1.Taken together, these results demonstrate that a 
prolonged stimulation of mitochondrial activity induces muscle atrophy. In 
addition, these data underline the importance of a tight control of p43 
expression and suggest that a deregulation of the direct T3 mitochondrial 
pathway could be one of the parameters involved in the occurrence of sarcopenia.