Moderate Endurance Exercise Increases Arrhythmia Susceptibility and Modulates Cardiac Structure and Function in a Sexually Dimorphic Manner.

BACKGROUND: Although moderate endurance exercise has been reported to improve cardiovascular health, its effects on cardiac structure and function are not fully characterized, especially with respect to sexual dimorphism. We aimed to assess the effects of moderate endurance exercise on cardiac physiology in male versus female mice. METHODS AND RESULTS: C57BL/6J mice of both sexes were run on a treadmill for 6 weeks. ECG and echocardiography were performed every 2 weeks. After 6 weeks of exercise, mice were euthanized, and triple parametric optical mapping was performed on Langendorff perfused hearts to assess cardiac electrophysiology. Arrhythmia inducibility was tested by programmed electrical stimulation. Left ventricular tissue was fixed, and RNA sequencing was performed to determine exercise-induced transcriptional changes. Exercise-induced left ventricular dilatation was observed in female mice alone, as evidenced by increased left ventricular diameter and reduced left ventricular wall thickness. Increased cardiac output was also observed in female exercised mice but not males. Optical mapping revealed further sexual dimorphism in exercise-induced modulation of cardiac electrophysiology. In female mice, exercise prolonged action potential duration and reduced voltage-calcium influx delay. In male mice, exercise reduced the calcium decay constant, suggesting faster calcium reuptake. Exercise increased arrhythmia inducibility in both male and female mice; however, arrhythmia duration was increased only in females. Lastly, exercise-induced transcriptional changes were sex dependent: females and males exhibited the most significant changes in contractile versus metabolism-related genes, respectively. CONCLUSIONS: Our data suggest that moderate endurance exercise can significantly alter multiple aspects of cardiac physiology in a sex-dependent manner. Although some of these effects are beneficial, like improved cardiac mechanical function, others are potentially proarrhythmic.

Anthracycline cardiotoxicity is exacerbated by global p38ß genetic ablation in a sexually dimorphic manner but unaltered by cardiomyocyte-specific p38α loss.

Severe cardiotoxic effects limit the efficacy of doxorubicin (DOX) as a chemotherapeutic agent. Activation of intracellular stress signaling networks, including p38 mitogen-activated protein kinase (MAPK), has been implicated in DOX-induced cardiotoxicity (DIC). However, the roles of the individual p38 isoforms in DIC remain incompletely elucidated. We recently reported that global p38δ deletion protected female but not male mice from DIC, whereas global p38γ deletion did not significantly modulate it. Here we studied the in vivo roles of p38α and p38ß in acute DIC. Male and female mice with cardiomyocyte-specific deletion of p38α or global deletion of p38ß and their wild-type counterparts were injected with DOX. Survival and health were tracked for 10 days postinjection. Cardiac function was assessed by echocardiography and electrocardiography and fibrosis by Picrosirius red staining. Expression and activation of signaling proteins and inflammatory markers were measured by Western blot, phosphorylation array, and chemokine/cytokine array. Global p38ß deletion significantly aggravated DIC and worsened cardiac electrical and mechanical function deterioration in female mice. Mechanistically, DIC in p38ß-null female mice correlated with increased autophagy, sustained hyperactivation of proapoptotic JNK signaling, as well as remodeling of a myocardial inflammatory environment. In contrast, cardiomyocyte-specific deletion of p38α improved survival of DOX30-treated male mice 5 days posttreatment but did not influence cardiac function in DOX-treated male or female mice. Our data highlight the sex- and isoform-specific roles of p38α and p38ß MAPKs in DOX-induced cardiac injury and suggest a novel in vivo function of p38ß in protecting female mice from DIC.NEW & NOTEWORTHY We show that p38α and p38ß have distinct in vivo functions in a murine model of acute DIC. Specifically, although conditional cardiomyocyte-specific p38α deletion exhibited mild cardioprotective effects in male mice, p38ß deletion exacerbated the DOX cardiotoxicity in female mice. Our findings caution against employing pyridinyl imidazole inhibitors that target both p38α and p38ß isoforms as a cardioprotective strategy against DIC. Such an approach could have undesirable sex-dependent effects, including attenuating p38ß-dependent cardioprotection in females.