Exploring the Role of Exercise and the Lysosomal Cathepsin Family in the Regulation of Vascular-Musculoskeletal Degenerative Diseases.

Musculoskeletal degenerative diseases significantly compromise patient quality of life through muscle loss, bone fragility, and cartilage degeneration. Given the established link between vascular aging and musculoskeletal disorders, the vascular-skeletomuscular axis represents a complex network wherein conditions interact via mechanisms including impaired blood flow, inflammation, oxidative stress, and hormonal imbalances. As pharmacological interventions targeting lysosomal cathepsins face developmental and application challenges, exploring non-pharmacological alternatives becomes imperative. This review investigates the regulatory roles of the lysosomal cathepsin family, especially cathepsins B, K, and L, in musculoskeletal degenerative diseases and evaluates how exercise interventions modulate their activities. It proposes exercise as a viable non-pharmacological strategy to selectively influence lysosomal cathepsin functions, thereby offering therapeutic potential in managing vascular-musculoskeletal degenerative diseases. The review elucidates several key concepts: the intricate interaction between vascular aging and musculoskeletal degenerative pathologies; the pivotal roles of lysosomal cathepsins in disease progression through metabolic regulation, inflammatory modulation, macrophage polarization, and autophagy dysfunction; and the multifaceted mechanisms by which exercise influences cathepsin activity, including calcium homeostasis, cellular energy metabolism enhancement, inflammatory response reduction, autophagy stimulation, myokine secretion, and vascular function improvement. This comprehensive analysis provides novel insights into exercise as a selective modulator of lysosomal cathepsin activity, highlighting its significant potential for advancing diagnostic and clinical therapeutic approaches.