Myokines and mitochondrial function in cardiometabolic diseases

Cardiometabolic diseases (CMD) encompass a group of disorders sharing a common pathophysiology that increases the risk of cardiovascular disease and mortality. Key events underlying CMD pathophysiology include insulin resistance, low-grade inflammation, altered hormonal and myokine profiles, and mitochondrial dysfunction. The latter manifests as reduced mitochondrial mass and oxidative function, increased oxidative stress, altered Ca²⁺ handling and decreased mitochondrial membrane potential. Skeletal muscle plays a pivotal role in CMD pathophysiology through two main mechanisms: i) the storage and oxidation of energy substrates and ii) the release of myokines, which in turn modulate metabolism and mitochondrial function. Here, we propose that the unfavorable myokine profile associated with CMD pathophysiology leads to mitochondrial alterations, and that restoring a healthy myokine profile helps improve mitochondrial structure, function, and overall metabolic health. To test this idea, in this narrative review, we critically present evidence of an altered myokine profile in CMD and highlight the most important mitochondrial alterations in CMD before examining the direct effect of specific myokines on mitochondria and CMD-associated mitochondrial dysfunction. Finally, we summarize the effects of therapeutic interventions on both the myokine profile and mitochondrial function, also appraising human trials that use myokine-based interventions to improve CMD. We focus on molecular mechanisms and causal relationships, while also indicating novel perspectives in the field. Understanding the role of mitochondria in the effect of myokines on metabolic health may open new preventive and therapeutic strategies for addressing CMD more efficiently.