Clusterin, through exercise-mediated liver-heart crosstalk, promotes heart regeneration after myocardial infarction

Loss of cardiomyocytes drives cardiac remodeling and ultimately leads to heart failure, highlighting the need to promote cardiac regeneration. Exercise has been known to enhance cardiac repair and stimulate cardiomyocyte proliferation; however, the underlying mechanisms remain unclear. In this study, we demonstrated that exercise-induced exerkine clusterin mediates the pro-regenerative effects of running plasma on cardiac repair and cardiomyocyte proliferation following myocardial infarction (MI). Cardiac-specific Clu knockout attenuated, whereas clusterin overexpression enhanced, post-MI cardiac regeneration. Recombinant clusterin administration promoted heart regeneration in adult mice after MI. Mechanistically, clusterin activated NF-κB via proteasome-dependent IκBα degradation through direct binding with IκBα. Furthermore, the liver was identified as the major source of exercise-induced circulating clusterin; hepatocyte-specific Clu knockdown abolished the stimulatory effect of exercise plasma on cardiac regeneration. This study reveals a liver-heart crosstalk mechanism by which exercise-induced clusterin promotes cardiomyocyte proliferation, positioning clusterin as a potential therapeutic target for post-MI heart failure.