Baehr Leslie M, West Daniel W D, Marshall Andrea G, Marcotte George R, Baar Keith, Bodine Sue C
Veterans Affairs Northern California Health Care System, Mather, California.
Department of Physiology and Membrane Biology, University of California Davis, Davis, California; and.
J Appl Physiol (1985). 2017 May 1;122(5):1336-1350. doi: 10.1152/japplphysiol.00703.2016. Epub 2017 Mar 23.
Disuse is a potent inducer of muscle atrophy, but the molecular mechanisms driving this loss of muscle mass are highly debated. In particular, the extent to which disuse triggers decreases in protein synthesis or increases in protein degradation, and whether these changes are uniform across muscles or influenced by age, is unclear. We aimed to determine the impact of disuse on protein synthesis and protein degradation in lower limb muscles of varied function and fiber type in adult and old rats. Alterations in protein synthesis and degradation were measured in the soleus, medial gastrocnemius, and tibialis anterior (TA) muscles of adult and old rats subjected to hindlimb unloading (HU) for 3, 7, or 14 days. Loss of muscle mass was progressive during the unloading period, but highly variable (-9 to -38%) across muscle types and between ages. Protein synthesis decreased significantly in all muscles, except for the old TA. Atrophy-associated gene expression was only loosely associated with protein degradation as muscle RING finger-1, muscle atrophy F-box (MAFbx), and Forkhead box O1 expression significantly increased in all muscles, but an increase in proteasome activity was only observed in the adult soleus. MAFbx protein levels were significantly higher in the old muscles compared with adult muscles, despite the old having higher expression of microRNA-23a. These results indicate that adult and old muscles respond similarly to HU, and the greatest loss in muscle mass occurs in predominantly slow-twitch extensor muscles due to a concomitant decrease in protein synthesis and increase in protein degradation. In this study, we showed that age did not intensify the atrophy response to unloading in rats, but rather that the degree of atrophy was highly variable across muscles, indicating that changes in protein synthesis and protein degradation occur in a muscle-specific manner. Our data emphasize the importance of studying muscles of varying fiber-type and physiological function at multiple time points to fully understand the molecular mechanisms responsible for disuse atrophy.
废用是肌肉萎缩的一个重要诱因，但导致肌肉质量丧失的分子机制仍存在很大争议。具体而言，废用在多大程度上引发蛋白质合成减少或蛋白质降解增加，以及这些变化在不同肌肉中是否一致或受年龄影响，目前尚不清楚。我们旨在确定废用对成年和老年大鼠不同功能和纤维类型的下肢肌肉中蛋白质合成和蛋白质降解的影响。在成年和老年大鼠的比目鱼肌、内侧腓肠肌和胫骨前肌（TA）中，测量了经历3、7或14天后肢卸载（HU）的大鼠蛋白质合成和降解的变化。在卸载期间，肌肉质量的丧失是渐进性的，但在不同肌肉类型和不同年龄之间差异很大（-9%至-38%）。除老年TA外，所有肌肉中的蛋白质合成均显著下降。萎缩相关基因表达与蛋白质降解的关联较弱，因为肌肉环指蛋白-1、肌肉萎缩F盒（MAFbx）和叉头盒O1在所有肌肉中的表达均显著增加，但仅在成年比目鱼肌中观察到蛋白酶体活性增加。尽管老年大鼠中微小RNA-23a的表达较高，但老年肌肉中的MAFbx蛋白水平显著高于成年肌肉。这些结果表明，成年和老年肌肉对HU的反应相似，肌肉质量的最大损失发生在主要为慢肌纤维的伸肌中，这是由于蛋白质合成的同时减少和蛋白质降解的增加所致。在本研究中，我们表明年龄并未加剧大鼠对卸载的萎缩反应，而是萎缩程度在不同肌肉中差异很大，这表明蛋白质合成和蛋白质降解的变化是以肌肉特异性方式发生的。我们的数据强调了在多个时间点研究不同纤维类型和生理功能的肌肉以充分理解废用性萎缩相关分子机制的重要性。
