Carboxyl terminus of Hsp70‐interacting protein (CHIP) is required to modulate cardiac hypertrophy and attenuate autophagy during exercise

Abstract

The carboxyl terminus of HSP70-interacting protein (CHIP) is a ubiquitin ligase/co-chaperone critical for the maintenance of cardiac function. Mice lacking CHIP (CHIP −/−) suffer decreased survival, enhanced myocardial injury, and increased arrhythmias compared to wild type controls following challenge with cardiac ischemia reperfusion injury. Recent evidence implicates a role for CHIP in chaperone-assisted selective autophagy, a process that is associated with exercise-induced cardioprotection. To determine whether CHIP is involved in cardiac autophagy, we challenged CHIP −/− mice with voluntary exercise. CHIP −/− mice respond to exercise with an enhanced autophagic response that is associated with an exaggerated cardiac hypertrophy phenotype. No impairment of function was identified in the CHIP −/− mice by serial echocardiography over the five weeks of running, indicating that the cardiac hypertrophy was physiologic not pathologic in nature. It was further determined that CHIP plays a role in inhibiting Akt signaling and autophagy determined by autophagic flux in cardiomyocytes and in the intact heart. Taken together, cardiac CHIP appears to play a role in regulating autophagy during the development of cardiac hypertrophy, possibly by its role in supporting Akt signaling, induced by voluntary running in vivo.

Muscle RING finger-1 attenuates IGF-I-dependent cardiomyocyte hypertrophy by inhibiting JNK signaling

“…Female mice were assigned to either unloaded (no resistance) wheel running or sedentary control groups, as described previously (54). Mice were randomly assigned to running or sham control groups and monitored in parallel by echocardiography on conscious mice using a Visual Sonics Vevo 770 and 2100 ultrasound biomicroscopy system at baseline, 2 wk, and 5 wk, as described previously (55,56).…”

“…The role of ubiquitin ligases in the regulation of IGF-I signaling in the myocardium in vivo is the latest in the growing literature implicating the ubiquitin proteasome system in maintenance of cardiac function (34,36). Mice lacking the ubiquitin ligase and protein chaperone carboxyl terminus of heat shock protein 70-interacting protein (CHIP) exhibit an exaggerated cardiac hypertrophy in as little as 1 wk and as much as 5 wk of running, which parallels increases in increased phosphorylated Akt after IGF-I stimulation in vitro (54). Although these studies suggest an inhibitory role of CHIP in Akt activation, Akt was not found to be a direct CHIP substrate, which has yet to be identified.…”

Exercise Regulation of Marrow Fat in the Setting of PPARγ Agonist Treatment in Female C57BL/6 Mice

“…Mice in either diet group were allocated to an exercise intervention for 6 weeks as previously described (7,33). The groups were as follows: 1) regular diet (CTL); 2) CTL exercise (CTL-E); 3) Rosi; and 4) Rosi-E.…”

BRG1 and BRM SWI/SNF ATPases redundantly maintain cardiomyocyte homeostasis by regulating cardiomyocyte mitophagy and mitochondrial dynamics in vivo

“…Autophagic flux was determined in vivo from the titration of bafilomycin A1 as previously described 24 . Antibodies for LC3B isoforms (Sigma-Aldrich #L7543) and beclin were used for western immunoblot analysis of markers of autophagy (Cell Signaling #3495P, Beverly, MA).…”

“…TaqMan gene expression assays (Life Technologies) were performed using universal TaqMan master mix (Life Technologies #4304437) commercial probes, as described previously 24 .…”