Abmormal expression of mitochondrial gene in disuse-induced muscle atrophy

为了阐明微重力诱导的肌肉萎缩的机制，我们专注于肌球蛋白重链（MHC）降解和基因表达的萎缩腓肠肌新生大鼠暴露于16天的航天。太空飞行刺激了蛋白质的泛素化，包括MHC分子，以及肌肉中MHC降解片段的积累。与地面对照大鼠相比，航天飞行显著增加了肌肉中组织蛋白酶L、蛋白酶体组分（RC 2和RC 9）、聚泛素、泛素结合酶、NADH脱氢酶和16 S核糖体RNA的mRNA水平。μ-calpain、m-calpain、cathepsin B和cathepsin H mRNA水平未受航天飞行影响。尾吊10 d以上大鼠也出现了与航天大鼠相似的变化，提示MHC降解与蛋白酶体依赖的蛋白水解激活和线粒体基因表达异常密切相关。然后，我们试图通过补充氨基酸来改善悬浮引起的肌肉萎缩。胃内补充140毫克的半胱氨酸悬浮大鼠显着防止后肢肌肉重量的损失，通过抑制肌肉蛋白的泛素化。谷氨酰胺、丙氨酸或半胱氨酸蛋白酶抑制剂对萎缩作用不大。半胱氨酸可以抑制线粒体产生的活性氧自由基，因此补充半胱氨酸可以阻止悬浮诱导的肌肉蛋白泛素化。

To elucidate the mechanisms of microgravity-induced muscle atrophy, we focused on myosin heavy chain (MHC) degradation and gene expression in atrophied gastrocnemius muscles of neonatal rats exposed to 16-day spaceflight. The spaceflight stimulated ubiquitination of proteins, including a MHC molecule, and accumulation of MHC degradation fragments in the muscles. The spaceflight significantly increased mRNA levels of cathepsin L, proteasome components (RC2 and RC9), polyubiquitin, ubiquitin-conjugating enzyme, NADH dehydrogenase and 16S ribosome RNA in the muscles, compared with those of ground control rats. The levels of μ-calpain, m-calpain, cathepsin B and cathepsin H mRNAs were not changed by the spaceflight. Tail-suspension of rats for 10 days or longer also caused similar changes, as was observed in the spaceflight rats, suggesting that MHC degradation were closely associated with activation of proteasome-dependent proteolysis and abnormal expression of mitochondrial gene. We then tried to improve the suspension-induced muscle atrophy by amino acid supplementation. Intragastric supplementation of 140 mg of cysteine to suspended rats significantly prevented loss of the hindlimb muscle weight by suppressing ubiquitination of muscle protein. Adminstraton of glutamine, alanine or cysteine protease inhibitor had little effect on the atrophy. Cysteine may scavenge reactive oxygen radicals produced from mitochondria so that cysteine supplementation prevented suspension-induced ubiquitination of muscle protein.