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(Circulation Research. 2007;100:1079.)
© 2007 American Heart Association, Inc.

Integrative Physiology

Early Exercise Training Normalizes Myofilament Function and Attenuates Left Ventricular Pump Dysfunction in Mice With a Large Myocardial Infarction

Monique C. de Waard, Jolanda van der Velden, Virginie Bito, Semir Ozdemir, Liesbeth Biesmans, Nicky M. Boontje, Dick H.W. Dekkers, Kees Schoonderwoerd, Hans C.H. Schuurbiers, Rini de Crom, Ger J.M. Stienen, Karin R. Sipido, Jos M.J. Lamers, Dirk J. Duncker

From Experimental Cardiology (M.C.d.W., D.J.D.), Department of Cardiology, Thoraxcenter, Erasmus MC, University Medical Center Rotterdam, The Netherlands; Laboratory for Physiology (J.v.d.V., N.M.B., G.J.M.S.), VU University Medical Center, Amsterdam, The Netherlands; Laboratory of Experimental Cardiology (V.B., S.O., L.B., K.R.S.), University of Leuven, Belgium; Department of Biochemistry (D.H.W.D., J.M.J.L.), ⁵Cell Biology and Genetics (K.S., R.d.C.), Vascular Surgery (R.d.C.) and Laboratory for Hemodynamics Thoraxcenter (H.C.H.S.), Erasmus MC, University Medical Center Rotterdam, The Netherlands.

Correspondence to Dirk J. Duncker MD PhD, Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000 CA Rotterdam, The Netherlands. E-mail d.duncker{at}erasmusmc.nl

The extent and mechanism of the cardiac benefit of early exercise training following myocardial infarction (MI) is incompletely understood, but may involve blunting of abnormalities in Ca²⁺-handling and myofilament function. Consequently, we investigated the effects of 8-weeks of voluntary exercise, started early after a large MI, on left ventricular (LV) remodeling and dysfunction in the mouse. Exercise had no effect on survival, MI size or LV dimensions, but improved LV fractional shortening from 8±1 to 12±1%, and LVdP/dt_P30 from 5295±207 to 5794±207 mm Hg/s (both P<0.05), and reduced pulmonary congestion. These global effects of exercise were associated with normalization of the MI-induced increase in myofilament Ca²⁺-sensitivity (pCa₅₀=0.037). This effect of exercise was PKA-mediated and likely because of improved ß₁-adrenergic signaling, as suggested by the increased ß₁-adrenoceptor protein (48%) and cAMP levels (36%; all P<0.05). Exercise prevented the MI-induced decreased maximum force generating capacity of skinned cardiomyocytes (F_max increased from 14.3±0.7 to 18.3±0.8 kN/m² P<0.05), which was associated with enhanced shortening of unloaded intact cardiomyocytes (from 4.1±0.3 to 7.0±0.6%; P<0.05). Furthermore, exercise reduced diastolic Ca²⁺-concentrations (by 30%, P<0.05) despite the unchanged SERCA2a and PLB expression and PLB phosphorylation status. Importantly, exercise had no effect on Ca²⁺-transient amplitude, indicating that the improved LV and cardiomyocyte shortening were principally because of improved myofilament function. In conclusion, early exercise in mice after a large MI has no effect on LV remodeling, but attenuates global LV dysfunction. The latter can be explained by the exercise-induced improvement of myofilament function.

Key Words: cardiac function • cardiomyocytes • exercise training • heart failure

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