ムジュウリョク ニヨル キンイシュク ト ソノ ショクジ ニヨル ヨボウ
Mechanism of microgravity-induced muscle atrophy and development of effective space food against the atrophy
池本, 円 徳島大学医学部栄養生理学講座
加納, 美保子 徳島大学医学部栄養生理学講座
浅野間, 友紀 徳島大学医学部栄養生理学講座
The elucidate the mechanisms of microgravity-induced muscle atrophy, we focused on fast-type myosin heavy chain (MHC) degradation and expression of proteases in atrophied gastrocnemius muscles of neonatal rats exposed to 16-d spaceflight (STS-90). The spaceflight stimulated ubiquitination of proteins, including a MHC molecule, and accumulation of MHC degradation fragments in the muscles. Semi-quantitative RT-PCR revealed that the spaceflight significantly increased mRNA levels of cathepsin L, proteasome components, polyubiquitin, and ubiquitin-conjugating enzyme 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. We also found that tail-suspension of rats for 10 d or longer caused the ubiquitination and degradation of MHC in gastrocnemius muscle, as was observed in the spaceflight rats. In the muscle of suspended rats, these changes were closely associated with activation of proteasome and up-regulation of expression of mRNA for the proteasome components and polyubiquitin. Administration of a cysteine protease inhibitor, E-64, to the suspended rats did not prevent the MHC degradation. Our results suggest that spaceflight induces the degradation of muscle contractile proteins, including MHC, possibly through a ubiquitin-dependent proteolytic pathway. To elucidate whether the ubiquitination was accompanied with oxidative stress, we measured markers for oxidative stress, such as thiobarbituric acid-reactive substance (TBARS) and glutathione disulfide (GSSG), in gastrocnemius muscle of tail-suspended rats. Glutathione (GSH) concentration in the muscle significantly decreased from Day 5 and reached a minimum value on Day 10. Tail-suspension reciprocally increased concentrations of TBARS and GSSG in parallel with enhancement of protein ubiquitination, suggesting that oxidative stress may play an important role in protein ubiquitination caused by tail-suspension. To prevent ubiquitination associated with oxidative stress, we also administered an antioxidative nutrient, cysteine, to tail-suspended rats. Intragastric supplementation of 140 mg/rat of cysteine for 2 wks or longer normalized the ratio of GSH to GSSG in the muscle and suppressed protein ubiquitination and MHC fragmentation, compared with supplementation of the equimolar amount of alanine. The cysteine supplementation significantly suppressed the loss of hindlimb muscle weight. Our results also suggest that supplementation of antioxidative nutrients, such as cysteine, may be beneficial to prevent ubiquitination of muscle protein caused by unweighting.
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