| First Author | Karam CN | Year | 2017 |
| Journal | Am J Physiol Heart Circ Physiol | Volume | 312 |
| Issue | 4 | Pages | H681-H690 |
| PubMed ID | 28130336 | Mgi Jnum | J:241077 |
| Mgi Id | MGI:5897704 | Doi | 10.1152/ajpheart.00469.2016 |
| Citation | Karam CN, et al. (2017) Peroxisome proliferator-activated receptor-alpha expression induces alterations in cardiac myofilaments in a pressure-overload model of hypertrophy. Am J Physiol Heart Circ Physiol 312(4):H681-H690 |
| abstractText | 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 overexpress a relatively low level of the peroxisome proliferator-activated receptor alpha (PPARalpha), and nontransgenic (NTg) littermates. The mice (NTg-T and Tg-T) were stressed by transverse aortic constriction (TAC) and compared with shams (NTg-S and Tg-S). There was an approximate 4-fold increase in PPARalpha expression in Tg-S compared with NTg-S, but Tg-T hearts showed the same PPARalpha expression as NTg-T. Expression of PPARalpha did not alter the hypertrophic response to TAC but did reduce ejection fraction (EF) in Tg-T hearts compared with other groups. The rate of actomyosin ATP hydrolysis was significantly higher in Tg-S skinned fiber bundles compared with all other groups. Tg-T hearts showed an increase in phosphorylation of specific sites on cardiac myosin binding protein-C (cMyBP-C) and beta-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 PPARalpha 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.NEW & NOTEWORTHY Data presented here demonstrate novel signaling to sarcomeric proteins by chronic alterations in fatty acid metabolism induced by PPARalpha. The mechanism involves modifications of key myofilament regulatory proteins modifying cross-bridge dynamics with differential effects in controls and hearts stressed by pressure overload. |
