Stocks Ben, Quesada Julia Prats, Mozzicato Anthony M, Jacob Carolina, Jensen Simone, MacGregor Kirstin A, Bangsbo Jens, Zierath Juleen R, Hostrup Morten, Deshmukh Atul S
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
Sci Adv. 2025 Jan 31;11(5):eadp8608. doi: 10.1126/sciadv.adp8608.
The skeletal muscle interstitial space is the extracellular region around myofibers and mediates cross-talk between resident cell types. We applied a proteomic workflow to characterize the human skeletal muscle interstitial fluid proteome at rest and in response to exercise. Following exhaustive exercise, markers of skeletal muscle damage accumulate in the interstitial space followed by the appearance of immune cell-derived proteins. Among the proteins up-regulated after exercise, we identified cathelicidin-related antimicrobial peptide (CAMP) as a bioactive molecule regulating muscle fiber development. Treatment with the bioactive peptide derivative of CAMP (LL-37) resulted in the growth of larger C2C12 skeletal muscle myotubes. Phosphoproteomics revealed that LL-37 activated pathways central to muscle growth and proliferation, including phosphatidylinositol 3-kinase, AKT serine/threonine kinase 1, mitogen-activated protein kinases, and mammalian target of rapamycin. Our findings provide a proof of concept that the interstitial fluid proteome is quantifiable via microdialysis sampling in vivo. These data highlight the importance of cellular communication in the adaptive response to exercise.
骨骼肌间质空间是肌纤维周围的细胞外区域，介导驻留细胞类型之间的相互作用。我们应用蛋白质组学方法来表征静息状态下以及运动反应中的人体骨骼肌间质液蛋白质组。力竭运动后，骨骼肌损伤标志物在间质空间中积累，随后出现免疫细胞衍生的蛋白质。在运动后上调的蛋白质中，我们鉴定出与cathelicidin相关的抗菌肽（CAMP）是一种调节肌纤维发育的生物活性分子。用CAMP的生物活性肽衍生物（LL-37）处理导致更大的C2C12骨骼肌肌管生长。磷酸蛋白质组学显示，LL-37激活了肌肉生长和增殖的核心通路，包括磷脂酰肌醇3激酶、AKT丝氨酸/苏氨酸激酶1、丝裂原活化蛋白激酶和雷帕霉素哺乳动物靶蛋白。我们的研究结果提供了一个概念证明，即间质液蛋白质组可通过体内微透析采样进行定量分析。这些数据突出了细胞通讯在运动适应性反应中的重要性。
