Cachexia Research Laboratory, Exercise Science Research Center, Department of Health, Human Performance and Recreation, University of Arkansas, Fayetteville, AR, USA.
Exercise Muscle Biology Laboratory, Exercise Science Research Center, Department of Health, Human Performance and Recreation, University of Arkansas, Fayetteville, AR, USA.
J Cachexia Sarcopenia Muscle. 2021 Dec;12(6):2056-2068. doi: 10.1002/jcsm.12809. Epub 2021 Sep 29.
Disuse decreases muscle size and is predictive of mortality across multiple pathologies. Detriments to mitochondrial function are hypothesized to underlie disuse-induced muscle atrophy. Little data exist on early mechanisms contributing to onset of these pathologies, nor is it known how they differ between sexes. The purpose of this study was to examine differential and conserved responses to mitochondrial quality control in male and female mice during the development and progression of disuse-induced atrophy.
One hundred C57BL/6J mice (50 male and 50 female) were hindlimb unloaded to induce disuse atrophy for 0 (con), 24, 48, 72, or 168 h. At designated time-points, extensor digitorum longus, gastrocnemius, and soleus muscles were collected for analysis of mitochondrial quality control markers.
One hundred sixty-eight hours of disuse resulted in 25% lower oxidative muscle fibre CSA in both male (P = 0.003) and female (P = 0.02) mice without any differences due to disuse in glycolytic fibres. In male mice, 48 h of unloading was sufficient to result in ~67% greater mitochondrial oxidative stress as assessed by the reporter gene pMitoTimer compared with 0 h (P = 0.002), this mitochondrial stress preceded detectable muscle loss. However in female mice, mitochondrial oxidative stress did not occur until 168 h of disuse (40% greater mitochondrial oxidative stress in 168 h compared with 0 h of disuse, P < 0.0001). Blunted oxidative stress in female mice appeared to coincide with greater inductions of autophagy and mitophagy in female mice (3-fold greater BNIP3 and ~6-fold greater LC3II/I ratio P < 0.0001 and P = 0.038 respectively). Male mice overall had greater reactive oxygen species (ROS) production compared with female mice. Female mice had a greater induction of ROS within 24 h of disuse (4-fold greater compared with 0 h, P < 0.0001); whereas male mice did not have greater ROS production until 168 h of disuse (~2-fold greater, P < 0.0001). Although all muscle types exhibited some alterations to mitochondrial quality control, such as increased markers of mitophagy and fission, the soleus muscle in both male and female mice exhibited consistent alterations to various markers of mitochondrial quality. Markers of mitochondrial translation were approximately 30-50% lower within 24 h of unloading in both male and female soleus muscle (P value ranges: <0.0001-0.03).
Disuse negatively affects mitochondria differentially between sexes during development of muscle wasting. Acutely, female mice may forgo muscle mass to maintain mitochondrial quality compared with male mice. These differences may contribute to divergent clinical manifestations of atrophy.
失用会导致肌肉萎缩，这在多种病理情况下都与死亡率有关。线粒体功能受损被认为是失用性肌肉萎缩的基础。关于导致这些病理的早期机制的数据很少，也不知道它们在性别之间有何不同。本研究的目的是探讨雄性和雌性小鼠在失用性萎缩发展和进展过程中，线粒体质量控制的差异和保守反应。
100 只 C57BL/6J 小鼠（50 只雄性和 50 只雌性）进行后肢去负荷以诱导失用性萎缩，时间分别为 0（对照）、24、48、72 或 168 小时。在指定的时间点，收集伸趾长肌、比目鱼肌和跖肌，以分析线粒体质量控制标志物。
168 小时的失用导致雄性（P=0.003）和雌性（P=0.02）小鼠的氧化肌纤维 CSA 降低约 25%，但失用对糖酵解纤维没有任何影响。在雄性小鼠中，48 小时的去负荷足以导致线粒体氧化应激增加约 67%，这可以通过报告基因 pMitoTimer 来评估（与 0 小时相比，P=0.002），这种线粒体应激先于可检测到的肌肉损失。然而，在雌性小鼠中，线粒体氧化应激直到失用 168 小时才发生（与失用 0 小时相比，168 小时的线粒体氧化应激增加约 40%，P<0.0001）。雌性小鼠中氧化应激的减弱似乎与雌性小鼠中自噬和线粒体自噬的更大诱导同时发生（BNIP3 增加约 3 倍，LC3II/I 比值增加约 6 倍，P<0.0001 和 P=0.038）。与雌性小鼠相比，雄性小鼠整体产生更多的活性氧（ROS）。雌性小鼠在失用 24 小时内产生更多的 ROS（与 0 小时相比，增加约 4 倍，P<0.0001）；而雄性小鼠直到失用 168 小时才产生更多的 ROS（增加约 2 倍，P<0.0001）。尽管所有肌肉类型都表现出一些线粒体质量控制的改变，如增加自噬和裂变的标志物，但雄性和雌性小鼠的跖肌都表现出各种线粒体质量标志物的一致改变。在失用后 24 小时内，雄性和雌性跖肌中的线粒体翻译标志物降低约 30-50%（P 值范围：<0.0001-0.03）。
在肌肉萎缩的发展过程中，失用对雄性和雌性的线粒体有不同的影响。急性失用时，雌性小鼠可能会放弃肌肉质量以维持线粒体质量，而雄性小鼠则不会。这些差异可能导致萎缩的临床症状不同。
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