Clinical School, University of Cambridge, Cambridge, United Kingdom.
Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota.
Am J Physiol Cell Physiol. 2021 May 1;320(5):C681-C688. doi: 10.1152/ajpcell.00462.2020. Epub 2021 Feb 10.
Skeletal muscle mitochondria are highly adaptable, highly dynamic organelles that maintain the functional integrity of the muscle fiber by providing ATP for contraction and cellular homeostasis (e.g., Na/K ATPase). Emerging as early modulators of inflammation, mitochondria sense and respond to cellular stress. Mitochondria communicate with the environment, in part, by release of physical signals called mitochondrial-derived damage-associated molecular patterns (mito-DAMPs) and deviation from routine function (e.g., reduced ATP production, Ca overload). When skeletal muscle is compromised, mitochondria contribute to an acute inflammatory response necessary for myofibril regeneration; however, exhaustive signaling associated with altered or reduced mitochondrial function can be detrimental to muscle outcomes. Here, we describe changes in mitochondrial content, structure, and function following skeletal muscle injury and disuse and highlight the influence of mitochondria-cytokine crosstalk on muscle regeneration and recovery. Although the appropriate therapeutic modulation following muscle stressors remains unknown, retrospective gene expression analysis reveals that interleukin-6 (IL-6), interleukin-1β (IL-1β), chemokine C-X-C motif ligand 1 (CXCL1), and monocyte chemoattractant protein 1 (MCP-1) are significantly upregulated following three unique muscle injuries. These cytokines modulate mitochondrial function and execute bona fide pleiotropic roles that can aid functional recovery of muscle, however, when aberrant, chronically disrupt healing partly by exacerbating mitochondrial dysfunction. Multidisciplinary efforts to delineate the opposing regulatory roles of inflammatory cytokines in the muscle mitochondrial environment are required to modulate regenerative behavior following skeletal muscle injury or disuse. Future therapeutic directions to consider include quenching or limited release of mito-DAMPs and cytokines present in cytosol or circulation.
骨骼肌线粒体是高度适应、高度动态的细胞器，通过为收缩和细胞内稳态（例如，Na/K ATP 酶）提供 ATP 来维持肌肉纤维的功能完整性。线粒体作为炎症的早期调节剂而出现，能够感知和响应细胞应激。线粒体通过释放物理信号（称为线粒体来源的损伤相关分子模式（mito-DAMPs））和偏离常规功能（例如，减少 ATP 产生、Ca 过载）与环境进行通讯。当骨骼肌受损时，线粒体有助于肌原纤维再生所需的急性炎症反应；然而，与改变或减少线粒体功能相关的过度信号可能对肌肉结果有害。在这里，我们描述了骨骼肌损伤和废用后线粒体含量、结构和功能的变化，并强调了线粒体-细胞因子串扰对肌肉再生和恢复的影响。尽管肌肉应激后适当的治疗调节仍然未知，但回顾性基因表达分析表明，白细胞介素 6 (IL-6)、白细胞介素 1β (IL-1β)、趋化因子 C-X-C 基序配体 1 (CXCL1) 和单核细胞趋化蛋白 1 (MCP-1) 在三种独特的肌肉损伤后显著上调。这些细胞因子调节线粒体功能并执行真正的多效性作用，可以帮助肌肉的功能恢复，但是，当异常时，它们会通过加剧线粒体功能障碍而慢性破坏愈合。需要进行多学科努力来描绘炎症细胞因子在肌肉线粒体环境中的对立调节作用，以调节骨骼肌损伤或废用后的再生行为。未来可以考虑的治疗方向包括淬灭或限制细胞溶质或循环中存在的 mito-DAMPs 和细胞因子的释放。
