Laboratory of Muscle Biology and Sarcopenia, Department of Exercise Physiology, West Virginia University School of Medicine, Morgantown, WV, USA 26506.
Center for Muscle, Metabolism and Neuropathology, Division of Rehabilitation Sciences, College of Health Professions, University of Tennessee Health Science Center, Memphis, TN, USA 38163.
Oxid Med Cell Longev. 2020 Jul 23;2020:3938672. doi: 10.1155/2020/3938672. eCollection 2020.
Beta-hydroxy-beta-methylbutyrate (HMB), a naturally occurring leucine metabolite, has been shown to attenuate plantar flexor muscle loss and increase myogenic stem cell activation during reloading after a period of significant muscle wasting by disuse in old rodents. However, it was less clear if HMB would alter dorsiflexor muscle response to unloading or reloading when there was no significant atrophy that was induced by unloading. In this study, we tested if calcium HMB (Ca-HMB) would improve muscle function and alter apoptotic signaling in the extensor digitorum longus (EDL) of aged animals that were unloaded but did not undergo atrophy. The EDL muscle was unloaded for 14 days by hindlimb suspension (HS) in aged (34-36 mo.) male Fisher 344 × Brown Norway rats. The rats were removed from HS and allowed normal cage ambulation for 14 days of reloading (R). Throughout the study, the rats were gavaged daily with 170 mg of Ca-HMB or water 7 days prior to HS, then throughout 14 days of HS and 14 days of recovery after removing HS. The animals' body weights were significantly reduced by ~18% after 14 days of HS and continued to decline by ~22% during R as compared to control conditions; however, despite unloading, EDL did not atrophy by HS, nor did it increase in mass after R. No changes were observed in EDL twitch contraction time, force production, fatigue resistance, fiber cross-sectional area, or markers of nuclear apoptosis (myonuclei + satellite cells) after HS or R. While HS and R increased the proapoptotic Bax protein abundance, BCL-2 abundance was also increased as was the frequency of TUNEL-positive myonuclei and satellite cells, yet muscle mass and fiber cross-sectional area did not change and Ca-HMB treatment had no effect reducing apoptotic signaling. These data indicate that (i) increased apoptotic signaling preceded muscle atrophy or occurred without significant EDL atrophy and (ii) that Ca-HMB treatment did not improve EDL signaling, muscle mass, or muscle function in aged rats, when HS and R did not impact mass or function.
β-羟基-β-甲基丁酸（HMB）是一种天然存在的亮氨酸代谢物，已被证明可减轻老年啮齿动物因废用导致的肌肉大量消耗后重新加载时的跖屈肌损失，并增加成肌干细胞的激活。然而，当废用引起的肌肉萎缩不明显时，HMB 是否会改变背屈肌对卸载或重新加载的反应尚不清楚。在这项研究中，我们测试了钙 HMB（Ca-HMB）是否会改善卸载但未发生萎缩的老年动物伸肌（EDL）的肌肉功能并改变其凋亡信号。EDL 肌肉通过后肢悬吊（HS）在老年（34-36 月龄）雄性 Fisher 344×Brown Norway 大鼠中被卸载 14 天。大鼠从 HS 中取出，并允许在重新加载（R）的 14 天内正常笼内活动。在整个研究过程中，大鼠在 HS 前 7 天每天用 170mg Ca-HMB 或水灌胃，然后在整个 HS 期间 14 天和从 HS 中取出后的 14 天内进行灌胃。与对照条件相比，HS 后 14 天大鼠体重显著下降约 18%，R 期间继续下降约 22%；然而，尽管卸载，EDL 并未因 HS 而萎缩，R 后也未增加。HS 或 R 后，EDL 的 twitch 收缩时间、力产生、抗疲劳性、纤维横截面积或核凋亡标志物（肌核+卫星细胞）均无变化。虽然 HS 和 R 增加了促凋亡 Bax 蛋白的丰度，但 BCL-2 的丰度也增加了，TUNEL 阳性肌核和卫星细胞的频率也增加了，但肌肉质量和纤维横截面积没有变化，Ca-HMB 治疗也没有减少凋亡信号。这些数据表明：（i）凋亡信号增加先于肌肉萎缩或在 EDL 萎缩不明显的情况下发生；（ii）当 HS 和 R 不影响质量或功能时，Ca-HMB 治疗并不能改善老年大鼠的 EDL 信号、肌肉质量或肌肉功能。
