Molecular Medicine Program, University of Utah, Salt Lake City, Utah, United States.
Department of Kinesiology, Nutrition and Health, Miami University, Oxford, Ohio, United States.
J Appl Physiol (1985). 2023 Apr 1;134(4):923-932. doi: 10.1152/japplphysiol.00444.2022. Epub 2023 Mar 2.
Timely and complete recovery of muscle mass and function following a bout of physical disuse are critical components of returning to normal activities of daily living and lifestyle. Proper cross talk between the muscle tissue and myeloid cells (e.g., macrophages) throughout the recovery period from disuse atrophy plays a significant role in the complete resolution of muscle size and function. Chemokine C-C motif ligand 2 (CCL2) has a critical function of recruiting macrophages during the early phase of muscle damage. However, the importance of CCL2 has not been defined in the context of disuse and recovery. Here, we utilized a mouse model of whole body CCL2 deletion (CCL2KO) and subjected them to a period of hindlimb unloading followed by reloading to investigate the importance of CCL2 on the regrowth of muscle following disuse atrophy using ex vivo muscle tests, immunohistochemistry, and fluorescence-activated cell sorting approaches. We show mice that lack CCL2 display an incomplete recovery of gastrocnemius muscle mass, myofiber cross-sectional area, and EDL muscle contractile characteristics during the recovery from disuse atrophy. The soleus and plantaris had limited impact as a result of CCL2 deficiency suggesting a muscle-specific effect. Mice that lack CCL2 have decreased skeletal muscle collagen turnover, which may be related to defects in muscle function and stiffness. In addition, we show that the recruitment of macrophages to gastrocnemius muscle was dramatically reduced in CCL2KO mice during the recovery from disuse atrophy, which likely precipitated poor recovery of muscle size and function and aberrant collagen remodeling. We provide evidence that the whole body loss of CCL2 in mice has adverse impacts on whole body function and skeletal muscle-specific contractile characteristics and collagen content. These defects in muscle function worsened during the recovery from disuse atrophy and corresponded with decreased recovery of muscle mass. We conclude that the absence of CCL2 decreased recruitment of proinflammatory macrophages to the muscle during the regrowth phase following disuse atrophy resulting in impaired collagen remodeling events and full resolution of muscle morphology and function.
在经历一段时间的体力不活动后，及时且完全地恢复肌肉质量和功能是恢复日常生活和生活方式正常活动的关键组成部分。在不活动萎缩的恢复期内，肌肉组织和髓样细胞（例如巨噬细胞）之间的适当交流在完全解决肌肉大小和功能方面起着重要作用。趋化因子 C-C 基序配体 2（CCL2）在肌肉损伤的早期阶段具有招募巨噬细胞的关键功能。然而，在不活动和恢复的背景下，CCL2 的重要性尚未确定。在这里，我们利用全身性 CCL2 缺失（CCL2KO）的小鼠模型，并对其进行后肢去负荷，然后再进行加载，以使用离体肌肉测试，免疫组织化学和荧光激活细胞分选方法来研究 CCL2 在不活动萎缩后肌肉再生中的重要性。我们发现，缺乏 CCL2 的小鼠在从不活动萎缩中恢复时，表现出比目鱼肌质量，肌纤维横截面积和 EDL 肌肉收缩特性的不完全恢复。由于 CCL2 缺乏，比目鱼肌和跖肌的影响有限，这表明这是一种肌肉特异性作用。缺乏 CCL2 的小鼠骨骼肌胶原周转率降低，这可能与肌肉功能和僵硬缺陷有关。此外，我们还表明，在不活动萎缩恢复期，CCL2KO 小鼠的巨噬细胞向比目鱼肌的募集明显减少，这可能导致肌肉大小和功能恢复不良以及胶原重塑异常。我们提供的证据表明，CCL2 在小鼠中的全身性缺失对全身功能和骨骼肌特定的收缩特性以及胶原含量具有不利影响。这些肌肉功能缺陷在不活动萎缩的恢复期恶化，并与肌肉质量的恢复减少相对应。我们得出的结论是，缺乏 CCL2 会减少在不活动萎缩后的再生阶段向肌肉募集促炎巨噬细胞，从而导致胶原重塑事件受损以及肌肉形态和功能无法完全恢复。
