Townsend Logan K, Wright David, Pyle W Glen
Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada.
Women's Health Research Institute Team at BC Women's Hospital + Health Centre, Vancouver, British Columbia, Canada.
FASEB J. 2025 Aug 31;39(16):e70950. doi: 10.1096/fj.202502431R.
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.
运动需要心脏快速反应以维持心血管功能。CapZ是心肌细胞中的一种关键应激反应蛋白。虽然其在病理应激反应中的作用已被研究，但它在运动生理反应中的作用尚不清楚。本研究检测了运动过程中CapZ的调节情况，以确定其在心脏反应中的重要性。雌性野生型或心脏CapZ缺陷转基因小鼠（“CapZ小鼠”）进行力竭游泳或跑步实验以及次最大强度跑步。力竭时间是运动能力的一项指标。次最大强度运动后，分离心肌细丝并检测CapZ、其调节蛋白和肌丝蛋白。使用肌动球蛋白MgATP酶分析评估肌丝功能，并用ProQ Diamond染色对蛋白磷酸化进行定量。总肌丝CapZ不受运动影响，但CapZIP增加和磷酸化CapZIP减少表明CapZ-肌动蛋白相互作用减弱。CapZ小鼠的肌丝CapZIP没有变化。在游泳和跑步实验中，CapZ小鼠的力竭时间都较短。野生型小鼠的肌动球蛋白MgATP酶活性得以维持，而CapZ缺陷则使其受损。运动增加了野生型小鼠的肌丝蛋白磷酸化，但转基因动物没有。CapZ小鼠中运动依赖性的肌丝PKC-α和-ε增加有所减轻。在CapZ缺陷的肌丝中，伴肌动蛋白/Tcap水平随运动显著降低，而野生型肌丝中的细肌丝调节蛋白2增加。这些数据表明，心脏CapZ是运动生理反应中的关键参与者，并且CapZ-肌动蛋白结合会随运动迅速改变。心脏CapZ减少会限制运动能力，损害肌丝调节，并导致收缩装置稳定性降低。
