title: Peroxisome proliferator-activated receptor-α expression induces alterations in cardiac myofilaments in a pressure-overload model of hypertrophy.
abstract: 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 α (PPARα), 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 PPARα expression in Tg-S compared with 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 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 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.NEW & NOTEWORTHYData presented here demonstrate novel signaling to sarcomeric proteins by chronic alterations in fatty acid metabolism induced by PPARα. The mechanism involves modifications of key myofilament regulatory proteins modifying cross-bridge dynamics with differential effects in controls and hearts stressed by pressure overload.
authors.affiliation: Department of Physiology & Biophysics, Center for Cardiovascular Research, University of Illinois at Chicago, Chicago, Illinois; and.
authors.forename: Chehade N
authors.initials: CN
authors.lastname: Karam
authors.affiliation: Department of Physiology & Biophysics, Center for Cardiovascular Research, University of Illinois at Chicago, Chicago, Illinois; and.
authors.forename: Chad M
authors.initials: CM
authors.lastname: Warren
authors.affiliation: Department of Physiology & Biophysics, Center for Cardiovascular Research, University of Illinois at Chicago, Chicago, Illinois; and.
authors.forename: Marcus
authors.initials: M
authors.lastname: Henze
authors.affiliation: Department of Physiology & Biophysics, Center for Cardiovascular Research, University of Illinois at Chicago, Chicago, Illinois; and.
authors.forename: Natasha H
authors.initials: NH
authors.lastname: Banke
authors.affiliation: Department of Physiology & Biophysics, Center for Cardiovascular Research, University of Illinois at Chicago, Chicago, Illinois; and.|Sanford Burnham Presbyterian Medical Discovery Institute, Orlando, Florida.
authors.forename: E Douglas
authors.initials: ED
authors.lastname: Lewandowski
authors.affiliation: Department of Physiology & Biophysics, Center for Cardiovascular Research, University of Illinois at Chicago, Chicago, Illinois; and solarorj@uic.edu.
authors.forename: R John
authors.initials: RJ
authors.lastname: Solaro
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D020013:Calcium Signaling / Q000235:genetics; D006332:Cardiomegaly / Q000209:etiology / Q000503:physiopathology*; D002352:Carrier Proteins / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D006321:Heart / Q000503:physiopathology; D006973:Hypertension / Q000150:complications / Q000503:physiopathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D009210:Myofibrils; D018995:Myosin Heavy Chains / Q000378:metabolism; D047493:PPAR alpha / Q000096:biosynthesis* / Q000235:genetics*; D010766:Phosphorylation; D013318:Stroke Volume; D000099163:Myosin Binding Protein C
chemical_list: D000251:Adenosine Triphosphatases; D002352:Carrier Proteins; D005227:Fatty Acids; D018995:Myosin Heavy Chains; D047493:PPAR alpha; D000099163:Myosin Binding Protein C
keywords: cMyBP-C; calcium; metabolism; phosphorylation; sarcomere mechanics