Cardiac CapZ regulation during acute exercise

Abstract

AbstractPurposeExercise 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 acute exercise and sought to determine its importance in the cardiac response to exercise.MethodsWildtype or cardiac CapZ-deficient transgenic mice were subjected to 20 min of swimming, or exhaustive exercise protocols. Time to exhaustion was a measurement of exercise capacity. Following submaximal exercise, cardiac myofilaments were isolated and probed for CapZ and key regulatory proteins. Myofilament function was assessed using an actomyosin MgATPase assay and total protein phosphorylation quantified with ProQ Diamond staining. Myofilament regulatory proteins following submaximal exercise were quantified by immunoblotting.ResultsTotal myofilament CapZ was unaffected by exercise but increased total CapZIP and decreased phosphorylated CapZIP indicated weakened CapZ-actin interaction. CapZ-deficient transgenic myofilaments lacked changes in CapZIP but BAG3 increased 10%. Time to exhaustion was lower in CapZ-deficient mice in both swimming and running protocols. Actomyosin MgATPase activity was maintained in wildtype mice and impaired with CapZ deficiency. Exercise increased the phosphorylation of several myofilament proteins in wildtype mice but not transgenic animals. Exercise-dependent Increases in myofilament PKC-α and -ε were mitigated in CapZ-deficient mice. Tcap levels decreased 39 ± 8% in CapZ-deficient myofilaments with exercise and leiomodin 2 increased 78 ± 28% in wildtype myofilaments.ConclusionsCardiac CapZ is a critical player in the physiological response to exercise. 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.