Skeletal muscle-heart crosstalk in chronic kidney disease: hierarchical signaling networks underlying myocardial metabolic reprogramming and fibrotic remodeling.

Cardiovascular disease is a major complication of chronic kidney disease (CKD) and often develops alongside skeletal muscle wasting and sarcopenia. These abnormalities are usually studied as separate consequences of CKD, but they may also be linked through shared systemic stressors and inter-organ communication. CKD exposes both skeletal muscle and the myocardium to a persistent uremic milieu characterized by toxin retention, chronic inflammation, oxidative stress, hypoxia, and metabolic disturbance. In this setting, skeletal muscle-heart crosstalk may shift from an adaptive homeostatic program to a maladaptive network that contributes to myocardial metabolic dysfunction and fibrotic remodeling. Under physiological conditions, and especially during exercise, skeletal muscle releases myokines and extracellular vesicles carrying miRNAs, proteins, and other regulatory molecules that support myocardial substrate utilization, mitochondrial function, and repair responses. In CKD, however, altered myokine profiles and dysregulated extracellular vesicle cargoes may act on cardiomyocytes, cardiac fibroblasts, and endothelial cells, promoting impaired metabolic flexibility, extracellular matrix deposition, and progressive cardiac remodeling. The heart may also feed back on skeletal muscle through cardiac-derived endocrine signals and neurohumoral pathways, further reinforcing muscle wasting and systemic dysfunction. In this review, we summarize current evidence on skeletal muscle-heart communication under physiological, exercise-related, and CKD-associated conditions, with emphasis on myokines, extracellular vesicles, and miRNA-mediated signaling. Better definition of this axis may help identify biomarkers and therapeutic targets for CKD-associated sarcopenia and cardiovascular disease.