title: Dissecting the role of the myofilament in diaphragm dysfunction during the development of heart failure in mice.
abstract: Dyspnea and reduced exercise capacity, caused, in part, by respiratory muscle dysfunction, are common symptoms in patients with heart failure (HF). However, the etiology of diaphragmatic dysfunction has not been identified. To investigate the effects of HF on diaphragmatic function, models of HF were surgically induced in CD-1 mice by transverse aortic constriction (TAC) and acute myocardial infarction (AMI), respectively. Assessment of myocardial function, isolated diaphragmatic strip function, myofilament force-pCa relationship, and phosphorylation status of myofilament proteins was performed at either 2 or 18 wk postsurgery. Echocardiography and invasive hemodynamics revealed development of HF by 18 wk postsurgery in both models. In vitro diaphragmatic force production was preserved in all groups while morphometric analysis revealed diaphragmatic atrophy and fibrosis in 18 wk TAC and AMI groups. Isometric force-pCa measurements of myofilament preparations revealed reduced Ca(2+) sensitivity of force generation and force generation at half-maximum and maximum Ca(2+) activation in 18 wk TAC. The rate of force redevelopment (ktr) was reduced in all HF groups at high levels of Ca(2+) activation. Finally, there were significant changes in the myofilament phosphorylation status of the 18 wk TAC group. This includes a decrease in the phosphorylation of troponin T, desmin, myosin light chain (MLC) 1, and MLC 2 as well as a shift in myosin isoforms. These results indicate that there are multiple changes in diaphragmatic myofilament function, which are specific to the type and stage of HF and occur before overt impairment of in vitro force production.
authors.affiliation: Department of Integrative Biology, University of Guelph, Guelph, Ontario, Canada; Cardiovascular Research Center, University of Guelph, Guelph, Ontario, Canada; and tgillis@uoguelph.ca.
authors.forename: Todd E
authors.initials: TE
authors.lastname: Gillis
authors.affiliation: Department of Integrative Biology, University of Guelph, Guelph, Ontario, Canada; Cardiovascular Research Center, University of Guelph, Guelph, Ontario, Canada; and.
authors.forename: Jordan M
authors.initials: JM
authors.lastname: Klaiman
authors.affiliation: Cardiovascular Research Center, University of Guelph, Guelph, Ontario, Canada; and Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Foster
authors.affiliation: Cardiovascular Research Center, University of Guelph, Guelph, Ontario, Canada; and Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada.
authors.forename: Mathew J
authors.initials: MJ
authors.lastname: Platt
authors.affiliation: Cardiovascular Research Center, University of Guelph, Guelph, Ontario, Canada; and Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada.
authors.forename: Jason S
authors.initials: JS
authors.lastname: Huber
authors.affiliation: Cardiovascular Research Center, University of Guelph, Guelph, Ontario, Canada; and Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada.
authors.forename: Melissa Y
authors.initials: MY
authors.lastname: Corso
authors.affiliation: Cardiovascular Research Center, University of Guelph, Guelph, Ontario, Canada; and Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada.
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Simpson
mesh_terms: D000818:Animals; D020013:Calcium Signaling; D003964:Diaphragm / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D018450:Disease Progression; D004417:Dyspnea / Q000378:metabolism* / Q000503:physiopathology; D006333:Heart Failure / Q000378:metabolism* / Q000503:physiopathology; D066298:In Vitro Techniques; D007537:Isometric Contraction; D008297:Male; D051379:Mice; D009124:Muscle Proteins / Q000378:metabolism*; D053580:Muscle Strength; D009203:Myocardial Infarction / Q000378:metabolism / Q000503:physiopathology; D009210:Myofibrils / Q000378:metabolism*; D010766:Phosphorylation; D013997:Time Factors; D020257:Ventricular Remodeling
chemical_list: D009124:Muscle Proteins
keywords: calcium-activated force generation; diaphragm function; heart failure; myofilament proteins; protein phosphorylation