Sarcopenia is characterized by reduced muscle strength and mass and a decline in muscle fiber diameter and amount of sarcomeric proteins. Sarcopenia involves the activation of the ubiquitin-proteasome system (UPS). MuRF-1 and atrogin-1 are E3 ubiquitin ligases belonging to UPS, leading to proteolysis mediated by the PSMB 5, 6, and 7 subunits of 20S proteasome. CCL5/RANTES induces a sarcopenic-like effect in muscle cells. The present work explored the impact of CCL5 on UPS components and the influence of UPS on its sarcopenic-like effect. We demonstrated that CCL5 increased MuRF-1 and atrogin-1 protein levels and mRNA levels of subunits PSMB 5, 6, and 7. We used the MG132 inhibitor to elucidate the role of the 20S proteasome in the CCL5-induced sarcopenic-like effect. This inhibitor prevented the decrease in troponin and MHC protein levels and partially prevented the reduction in the diameter of single-isolated FDB muscle fibers induced by CCL5. These findings indicate that CCL5 actively modulates the UPS. Moreover, our results show the direct participation of UPS in the sarcopenic-like phenotype induced by CCL5.

Sarcopenia corresponds to a decrease in muscle mass and strength. CCL5 is a new myokine whose expression, along with the CCR5 receptor, is increased in sarcopenic muscle. Therefore, we evaluated whether CCL5 and CCR5 induce a sarcopenic-like effect on skeletal muscle tissue and cultured muscle cells. Electroporation in the tibialis anterior (TA) muscle of mice was used to overexpress CCL5. The TA muscles were analyzed by measuring the fiber diameter, the content of sarcomeric proteins, and the gene expression of E3-ligases. C₂C₁₂ myotubes and single-isolated flexor digitorum brevis (FDB) fibers were also treated with recombinant CCL5 (rCCL5). The participation of CCR5 was evaluated using the antagonist maraviroc (MVC). Protein and structural analyses were performed. The results showed that TA overexpression of CCL5 led to sarcopenia by reducing muscle strength and mass, muscle-fiber diameter, and sarcomeric protein content, and by upregulating E3-ligases. The same sarcopenic phenotype was observed in myotubes and FDB fibers. We showed increased reactive oxygen species (ROS) production and carbonylated proteins, denoting oxidative stress induced by CCL5. When the CCR5 was antagonized, the effects produced by rCCL5 were prevented. In conclusion, we report for the first time that CCL5 is a novel myokine that exerts a sarcopenic-like effect through the CCR5 receptor.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a condition characterized by altered liver function due to fatty accumulation, which can lead to liver inflammation and, in advanced stages, liver carcinoma. MASLD is closely linked to several metabolic alterations, such as obesity and insulin resistance, which directly affect skeletal muscles and contribute to the development of sarcopenia. Sarcopenia is the loss of muscle mass and strength, leading to decreased physical performance in severe stages. Skeletal muscles secrete molecules known as myokines under various conditions, such as exercise or diseases like MASLD. These myokines modulate communication between the skeletal muscle and other tissues. These myokines regulate muscle mass and, in pathological conditions, contribute to the development of sarcopenia. Emerging evidence highlights the crucial role of myokines in regulating skeletal muscle metabolism and function in MASLD. Myokines influence muscle metabolism, inflammation, and insulin sensitivity, offering potential therapeutic targets for managing muscle atrophy and sarcopenia in the context of MASLD. Understanding the interaction between myokines and skeletal muscle may lead to novel interventions to mitigate MASLD progression and sarcopenia. This review examines the mechanisms by which myokines regulate skeletal muscle metabolism and function in the context of MASLD.