| 摘要: | 骨骼肌可藉由改變許多基因的表現來適應生理活動要求，例如進行離心收縮運動(eccentric exercise; E.E.)時；骨骼肌因表現豐富之peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α)，特別是在氧化型肌纖維，研究指出PGC-1α對於這類肌肉之生理適應，如短程運動、耐力訓練及急速運動以及某些病理狀態如精疲力竭運動等肌肉細胞之生理調節皆扮演重要角色。天然酚類化合物白黎蘆醇(resveratrol)主要存在葡萄皮中，它具有植物雌激素及抗氧化和抗發炎的特性，可能與調控核轉錄因子nuclear factor kappa-B (NF-κB)有關。白黎蘆醇亦可提升sirtuin (silent mating type information regulation 2 homolog ; SIRT1)之活性，SIRT1 是一種與細胞長壽、抗凋亡(apoptosis)及核苷酸修補因子有關的酵素，可能藉由SIR2 (哺乳動物中類似SIR2 的基因叫做SIRT1)延長細胞生命週期(cell cycle)，改善粒線體功能、能量代謝之恆定及增加細胞有氧容量等，這可由表現SIRT1 可促進跑步時間及提升肌肉耗氧量得到驗證。最近研究指出SIRT1 可功能性協同PGC-1α以促進細胞適應反應而扮演延長細胞生命，去除細胞氧化壓力及減少發炎細胞激素達到抗發炎等生理調適作用。另外我們發現 NF-κB也會因應離心收縮運動所誘導之急性細胞壓力(acute cellular stress) 而活化以媒介調整能量恆定之適應反應(adaptation)或引發代謝及氧化功能失調(metabolic & oxidative perturbation)之精疲力竭 (exhaustion) 反應；但其中NF-κB之角色與PGC-1α之間的關係並不清楚。由於白黎蘆醇具有增加 SIRT1 及修正NF-κB活性之能力，因此我們假設：白黎蘆醇可以經由調控SIRT1 活化PGC-1α以及 NF-κB 在活體動物離心收縮運動中之骨骼肌扮演調節能量平衡、抗疲勞提升耐力，或經由強化粒線體功能以增加氧化型肌纖維的數量，提升肌肉抗疲勞之適應功能，並提升離心收縮運動肌肉之耐受性以及抗肌肉細胞氧化壓力及減少發炎等作用。本計畫為探討白黎蘆醇上述之功效，因此擬逐年研究白黎蘆醇對動物骨骼肌離心收縮誘導之急速能量代謝變化、各種轉錄因子(如PPARα、MEF2、ERRα、 NRF1/2、GABP、FOXO1,3,4)依賴之適應或精疲力竭反應等不同運動生理狀態下，白黎蘆醇之保護作用及分子機轉，尤其是MAPKs (p38、JNK、ERK1/2)、AMPK 等與SIRT1 /PGC-1α以及NF-κB之間的相互關係探討。
Skeletal muscle adapts to physiological demands like eccentric exercise by altering a number of programs of gene expression. The expression of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α)is enriched in skeletal muscle, particularly in oxidative fiber types. Recently, the PGC-1αhas emerged as a key player in the regulation of physiological adaptations (e.g., short-term exercise, endurance training and acute bouts of exercise) and in some pathological conditions (e.g., exhaustion/cachexia). Resveratrol, a natural polyphenolic compound mainly found in the skin of grapes and well known for its phytoestrogenic, antioxidant and anti-inflammation properties, has been shown to modulate nuclear factor kappa B (NF-κB), a inflammation/ adaptation regulating factor, and increase SIRT1 activity, originally described as a factor regulating cell longevity, apoptosis and DNA repair, resulting in Sir2-dependent lifespan extension, impacting mitochondrial function and metabolic homeostasis, as well as increasing aerobic capacity, as evidenced by increased running time and consumption of oxygen in muscle fibers. SIRT1 has been shown to function together with PGC-1α to promote adaptation and play as a mediator of longevity, reactive oxygen species detoxification and anti-inflammation by reducing levels of circulating tumor necrosis factor-α and interleukin-6. Besides, NF-κB also responses to eccentric exercise-induced acute cellular stress for mediating adaptation or exhaustion by improving fuel homeostasis or causing metabolic/oxidative perturbation, but the relationship between PGC-1α and NF-κB remaining unclear. With capacity to increase SIRT1 activity and adjust NF-κB activity by resveratrol, we hypothesize that resveratrol could modulate PGC-1α functions, through SIRT1 activation,in vivo and ultimately impact on the regulation of energy homeostasis and adaptation of skeletal muscles in eccentric exercise via potently inducing mitochondrial activity that could be revealed in this project by elucidating the increase in oxidative type-muscle fibers, enhanced resistance to muscle fatigue, increased endurance to eccentric exercise, as well as reduced inflammation-associated muscle damage. Our goal aims to address the protective effect and underlying molecular mechanisms, as well as signaling pathways, especially mitogen activated protein kinase (MAPKs) and AMPK, as well as many transcriptional factors (PPARα, MEF2, ERRα, NRF1/2, GABP, FOXO1,3,4) on the regulation of PGC-1α and NF-κB of resveratrol under the acute substrate metabolism, transcriptionally-dependent adaptation, and cachexial exhaustion by eccentric exercise in rat skeletal muscle. |
