Cardiac CapZ Regulation During Acute Exercise in Female Mice

Exercise requires a rapid cardiac response to maintain cardiovascular function. CapZ is a critical stress-response protein in cardiac myocytes. While its role in the pathological stress response has been explored, its part in the physiological response to exercise is unknown. This study examined CapZ regulation during exercise to determine its importance in the cardiac response. Female wildtype or cardiac CapZ-deficient transgenic mice ("CapZ mice") were subjected to exhaustive swimming or running protocols and submaximal running. Time to exhaustion was a measurement of exercise capacity. Following submaximal exercise, cardiac myofilaments were isolated and probed for CapZ, its regulatory proteins, and myofilament proteins. Myofilament function was assessed using an actomyosin MgATPase assay, and protein phosphorylation was quantified with ProQ Diamond staining. Total myofilament CapZ was unaffected by exercise, but increased CapZIP and decreased phosphorylated CapZIP indicated weakened CapZ-actin interaction. Myofilaments from CapZ mice lacked changes in CapZIP. Time to exhaustion was lower in CapZ mice in both swimming and running protocols. Actomyosin MgATPase activity was maintained in wildtype mice and impaired with CapZ deficiency. Exercise increased myofilament protein phosphorylation in wildtype mice but not in transgenic animals. Exercise-dependent increases in myofilament PKC-α and -ε were mitigated in CapZ mice. Telethonin/Tcap levels decreased significantly in CapZ-deficient myofilaments with exercise, and leiomodin 2 increased in wildtype myofilaments. These data show Cardiac CapZ is a critical player in the physiological response to exercise and that CapZ-actin binding is rapidly altered with exercise. Decreased cardiac CapZ limits exercise capacity, impairs myofilament regulation, and leads to a less stable contractile apparatus.