title: Increased myocardial short-range forces in a rodent model of diabetes reflect elevated content of β myosin heavy chain.
abstract: Diastolic dysfunction is a clinically significant problem for patients with diabetes and often reflects increased ventricular stiffness. Attached cross-bridges contribute to myocardial stiffness and produce short-range forces, but it is not yet known whether these forces are altered in diabetes. In this study, we tested the hypothesis that cross-bridge-based short-range forces are increased in the streptozotocin (STZ) induced rat model of type 1 diabetes. Chemically permeabilized myocardial preparations were obtained from 12week old rats that had been injected with STZ or vehicle 4weeks earlier, and activated in solutions with pCa (=-log10[Ca(2+)]) values ranging from 9.0 to 4.5. The short-range forces elicited by controlled length changes were ∼67% greater in the samples from the diabetic rats than in the control preparations. This change was mostly due to an increased elastic limit (the length change at the peak short-range force) as opposed to increased passive muscle stiffness. The STZ-induced increase in short-ranges forces is thus unlikely to reflect changes to titin and/or collagen filaments. Gel electrophoresis showed that STZ increased the relative expression of β myosin heavy chain. This molecular mechanism can explain the increased short-ranges forces observed in the diabetic tissue if β myosin molecules remain bound between the filaments for longer durations than α molecules during imposed movements. These results suggest that interventions that decrease myosin attachment times may be useful treatments for diastolic dysfunction associated with diabetes.
authors.affiliation: Department of Physiology, Critical Care and Sleep Medicine, University of Kentucky, Lexington, KY 40536-0298, United States; Center for Muscle Biology, Critical Care and Sleep Medicine, University of Kentucky, Lexington, KY 40536-0298, United States.
authors.forename: Charles S
authors.initials: CS
authors.lastname: Chung
authors.affiliation: Department of Physiology, Critical Care and Sleep Medicine, University of Kentucky, Lexington, KY 40536-0298, United States; Center for Muscle Biology, Critical Care and Sleep Medicine, University of Kentucky, Lexington, KY 40536-0298, United States.
authors.forename: Mihail I
authors.initials: MI
authors.lastname: Mitov
authors.affiliation: Center for Muscle Biology, Critical Care and Sleep Medicine, University of Kentucky, Lexington, KY 40536-0298, United States; Division of Pulmonary, Critical Care and Sleep Medicine, University of Kentucky, Lexington, KY 40536-0298, United States.
authors.forename: Leigh Ann
authors.initials: LA
authors.lastname: Callahan
authors.affiliation: Department of Physiology, Critical Care and Sleep Medicine, University of Kentucky, Lexington, KY 40536-0298, United States; Center for Muscle Biology, Critical Care and Sleep Medicine, University of Kentucky, Lexington, KY 40536-0298, United States. Electronic address: k.s.campbell@uky.edu.
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Campbell
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D008297:Male; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology*; D018995:Myosin Heavy Chains / Q000032:analysis / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D024723:Ventricular Myosins / Q000032:analysis / Q000378:metabolism*
chemical_list: D024723:Ventricular Myosins; D018995:Myosin Heavy Chains
keywords: Biomechanics; Diastole; Myocardial stiffness