Overexpression of the mitochondrial T3 receptor induces skeletal muscle atrophy during aging.
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.
Casas
François
F
INRA, UMR866 Différenciation cellulaire et croissance, Montpellier, France. casasf@supagro.inra.fr
Pessemesse
Laurence
L
Grandemange
Stéphanie
S
Seyer
Pascal
P
Baris
Olivier
O
Gueguen
Naïg
N
Ramonatxo
Christelle
C
Perrin
Florence
F
Fouret
Gilles
G
Lepourry
Laurence
L
Cabello
Gérard
G
Wrutniak-Cabello
Chantal
C
D000375:Aging / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001835:Body Weight; D007473:Ion Channels / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D009119:Muscle Contraction; D009124:Muscle Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000254:growth & development / Q000473:pathology; D009133:Muscular Atrophy / Q000378:metabolism*; D018995:Myosin Heavy Chains / Q000378:metabolism; D009929:Organ Size; D018384:Oxidative Stress; D010805:Physical Conditioning, Animal; D010807:Physical Endurance; D020033:Protein Isoforms / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000378:metabolism*; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases; D000071246:Uncoupling Protein 2; D000071247:Uncoupling Protein 3
D000975:Antioxidants; D007473:Ion Channels; D024101:Mitochondrial Proteins; D009124:Muscle Proteins; D020033:Protein Isoforms; D011988:Receptors, Thyroid Hormone; D000070584:Tripartite Motif Proteins; D000071246:Uncoupling Protein 2; D000071247:Uncoupling Protein 3; D013482:Superoxide Dismutase; C486691:Fbxo32 protein, mouse; D044843:SKP Cullin F-Box Protein Ligases; C499084:Trim63 protein, mouse; D044767:Ubiquitin-Protein Ligases; D018995:Myosin Heavy Chains