Abstract
Titin-based myofilament stiffness is largely modulated by phosphorylation of its elastic I-band regions N2-Bus (decreases passive stiffness, PT) and PEVK (increases PT). Here, we tested the hypothesis that acute exercise changes titin phosphorylation and modifies myofilament stiffness. Adult rats were exercised on a treadmill for 15 min, untrained animals served as controls. Titin phosphorylation was determined by Western blot analysis using phosphospecific antibodies to Ser4099 and Ser4010 in the N2-Bus region (PKG and PKA-dependent. respectively), and to Ser11878 and Ser 12022 in the PEVK region (PKCα and CaMKIIδ-dependent, respectively). Passive tension was determined by step-wise stretching of isolated skinned cardiomyocytes to sarcomere length (SL) ranging from 1.9 to 2.4 μm and showed a significantly increased PT from exercised samples, compared to controls. In cardiac samples titin N2-Bus phosphorylation was significantly decreased by 40% at Ser4099, however, no significant changes were observed at Ser4010. PEVK phosphorylation at Ser11878 was significantly increased, which is probably mediated by the observed exercise-induced increase in PKCα activity. Interestingly, relative phosphorylation of Ser12022 was substantially decreased in the exercised samples. Surprisingly, in skeletal samples from acutely exercised animals we detected a significant decrease in PEVK phosphorylation at Ser11878 and an increase in Ser12022 phosphorylation; however, PKCα activity remained unchanged. In summary, our data show that a single exercise bout of 15 min affects titin domain phosphorylation and titin-based myocyte stiffness with obviously divergent effects in cardiac and skeletal muscle tissues. The observed changes in titin stiffness could play an important role in adapting the passive and active properties of the myocardium and the skeletal muscle to increased physical activity.
Highlights
The beneficial effect of regular physical activity on the cardiovascular system has been generally accepted
EXERCISE ACUTELY CHANGES CARDIAC TITIN PHOSPHORYLATION In order to characterize the effects of acute physical exercise on cardiac passive myofilament stiffness we determined the I-band phosphorylation status of titin using phosphosite-directed antibodies to Ser4010 (PKA-targeted) and Ser4099 (PKG-targeted) in the cardiac-specific N2-Bus region, and to Ser11878 and Ser12022 (PKCα and calmodulin-dependent protein kinase II δ (CaMKIIδ)-targeted) in the ubiquitously expressed part of the PEVK region
The results demonstrate that PT was significantly higher in cardiomyocytes isolated from acutely exercised animals, compared to controls (Figure 2A)
Summary
The beneficial effect of regular physical activity on the cardiovascular system has been generally accepted. In healthy humans, but in the setting of cardiovascular diseases, such as heart failure (HF), regular exercise training has been shown to improve cardiac outcome (reviewed in Leosco et al, 2013). According to the current hypotheses regular exercise at least partly restores the normal SNS activity and thereby improves cardiac function (Leosco et al, 2013). In aged subjects this exercise-induced improvement has been shown to be mediated by an enhanced left ventricular inotropic response to Ca2+ (Ehsani et al, 1991; Spina et al, 1998). Titin stiffening may support the length-dependent activation involved in the Frank Starling mechanism of the heart, which is responsible for the elevated cardiac output in response to increased preload (Methawasin et al, 2014)
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