Although alterations in fatty acid (FA) metabolism have been shown to have a negative impact on contractility of the hypertrophied heart, the targets of action remain elusive. In this study we compared the function of skinned fiber bundles from transgenic (Tg) mice, that over express a relatively low level of the peroxisome proliferator-activated receptor α (PPARα), and non-transgenic (NTg) littermates. The mice (NTg-T and Tg-T) were stressed by transverse aortic constriction (TAC) and compared to shams (NTg-S and Tg-S). There was an approximate 4 fold increase in PPARα expression in Tg-S compared to NTg-S, but Tg-T hearts showed the same PPARα expression as NTg-T. Expression of PPARα did not alter the hypertrophic response to TAC, but did reduce ejection fraction (EF) in Tg-T hearts compared to other groups. The rate of acto-myosin ATP hydrolysis was significantly higher in Tg-S skinned fiber bundles compared to all other groups. Tg-T hearts showed an increase in phosphorylation of specific sites on cardiac myosin binding protein-C (cMyBP-C) and β-myosin heavy chain isoform. These results advance our understanding of potential signaling to the myofilaments induced by altered FA metabolism under normal and pathological states. We demonstrate that chronic and transient PPARα activation during pathological stress alters myofilament response to Ca2+ through a mechanism that is possibly mediated by MyBP-C phosphorylation and myosin heavy chain isoforms.
- sarcomere mechanics
- myosin binding protein C
- Copyright © 2016, American Journal of Physiology-Heart and Circulatory Physiology