Michel J Max, Hettinger Zachary, Ambrosio Fabrisia, Egan Brendan, Roberts Michael D, Ferrando Arny A, Graham Zachary A, Bamman Marcas M
School of Kinesiology, Auburn University, Auburn, Alabama, USA.
Discovery Center for Musculoskeletal Recovery, Spaulding Rehabilitation Hospital, Harvard Medical School, Boston, Massachusetts, USA.
J Physiol. 2024 Jul 19. doi: 10.1113/JP284301.
Skeletal muscle wasting is the hallmark pathophysiological adaptation to unloading or disuse that demonstrates the dependency on frequent mechanical stimulation (e.g. muscle activation and subsequent loading) for homeostasis of normally load-bearing muscles. In the absence of mitigation strategies, no mammalian organism is resistant to muscle atrophy driven by unloading. Given the profound impact of unloading-induced muscle wasting on physical capacity, metabolic health and immune function; mitigation strategies during unloading and/or augmentation approaches during recovery have broad healthcare implications in settings of bed-bound hospitalization, cast immobilization and spaceflight. This topical review aims to: (1) provide a succinct, state-of-the-field summary of seminal and recent findings regarding the mechanisms of unloading-induced skeletal muscle wasting; (2) discuss unsuccessful vs. promising mitigation and recovery augmentation strategies; and (3) identify knowledge gaps ripe for future research. We focus on the rapid muscle atrophy driven by relatively short-term mechanical unloading/disuse, which is in many ways mechanistically distinct from both hypermetabolic muscle wasting and denervation-induced muscle atrophy. By restricting this discussion to mechanical unloading during which all components of the nervous system remain intact (e.g. without denervation models), mechanical loading requiring motor and sensory neural circuits in muscle remain viable targets for both mitigation and recovery augmentation. We emphasize findings in humans with comparative discussions of studies in rodents which enable elaboration of key mechanisms. We also discuss what is currently known about the effects of age and sex as biological factors, and both are highlighted as knowledge gaps and novel future directions due to limited research.
骨骼肌萎缩是对卸载或废用的标志性病理生理适应，表明正常承重肌肉的稳态依赖于频繁的机械刺激（如肌肉激活及随后的负荷）。在没有缓解策略的情况下，没有哺乳动物能够抵抗卸载引起的肌肉萎缩。鉴于卸载诱导的肌肉萎缩对身体机能、代谢健康和免疫功能有深远影响；在卸载期间的缓解策略和/或恢复期间的增强方法在卧床住院、石膏固定和太空飞行等情况下具有广泛的医疗意义。本专题综述旨在：（1）对关于卸载诱导骨骼肌萎缩机制的开创性和最新研究结果进行简洁的、该领域现状的总结；（2）讨论不成功与有前景的缓解和恢复增强策略；（3）确定适合未来研究的知识空白。我们关注由相对短期的机械卸载/废用驱动的快速肌肉萎缩，这在许多方面与高代谢性肌肉萎缩和去神经诱导的肌肉萎缩在机制上有所不同。通过将讨论限制在神经系统所有组成部分均保持完整的机械卸载期间（如无去神经模型），肌肉中需要运动和感觉神经回路的机械负荷仍然是缓解和恢复增强的可行靶点。我们强调人体研究结果，并对啮齿动物研究进行比较讨论，以阐明关键机制。我们还讨论了目前已知的年龄和性别作为生物学因素的影响，由于研究有限，两者均被突出显示为知识空白和新的未来方向。
