Casas François, Pessemesse Laurence, Grandemange Stéphanie, Seyer Pascal, Baris Olivier, Gueguen Naïg, Ramonatxo Christelle, Perrin Florence, Fouret Gilles, Lepourry Laurence, Cabello Gérard, Wrutniak-Cabello Chantal
INRA, UMR866 Différenciation cellulaire et croissance, Montpellier, France.
PLoS One. 2009 May 20;4(5):e5631. doi: 10.1371/journal.pone.0005631.
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.
在先前的研究中，我们鉴定了一条新的激素信号通路，该通路涉及一种作为线粒体转录因子的线粒体T3受体（p43）。在体外和体内研究中，我们已表明p43可增加线粒体转录和线粒体生物合成。此外，骨骼肌中p43的过表达可刺激线粒体呼吸，并诱导肌纤维的代谢和收缩特性发生转变，使其变得更具氧化性。在此，我们研究了衰老过程中p43过表达对小鼠骨骼肌的影响。我们报告称，p43过表达最初会增加线粒体质量。然而，在转基因小鼠2月龄时线粒体DNA出现早期增加之后，我们观察到线粒体DNA含量逐渐下降，在23月龄时相对于对照动物降低了2倍。此外，p43过表达诱导了一种氧化应激，其特征是股四头肌中脂质过氧化和蛋白质氧化大幅增加，尽管抗氧化酶活性（过氧化氢酶和超氧化物歧化酶）受到了刺激。另外，在6月龄时可检测到肌肉萎缩，这可能是通过两种肌肉特异性泛素连接酶E3（Atrogin-1/MAFbx和MuRF1）刺激泛素蛋白酶体途径所致。综上所述，这些结果表明线粒体活性的长期刺激会诱导肌肉萎缩。此外，这些数据强调了严格控制p43表达的重要性，并表明直接的T3线粒体信号通路失调可能是参与肌肉减少症发生的参数之一。
