Akt is essential for adaptive response of systolic left-ventricular function and aging-induced intolerance to exercise

Abstract

Purpose: Aging is one of the primary factors causing impaired diastolic left-ventricular function (DD). Clinical evidences demonstrate a sustained exercise (EX) ameliorates DD, and preclinical studies indicate the pivotal role of protein kinase Akt in aging. The purpose of the present study was to elucidate whether EX may exert therapeutic benefits on DD induced by aging and Akt may be essential for the EX-induced impact on DD. Methods: Male senescence-accelerated (SAM) mice [senescence-accelerated prone (P10) and -resistant (R1)] were allocated to exercise [EX; 60-min running on treadmill every single day for 6 months (P10-EX and R1-EX)] and exercise-free control groups (P10-ctl and R1-ctl). C57BL6 mice were subjected to the same EX protocol to elucidate influence of genetic background (C57-EX and C57-ctl). To elucidate the role of Akt in aging-induced changes in heart, analysis of aged Akt knockout mice (AktKO; 1 year-old and 2 year-old on C57BL6 background) were conducted. Cardiac diastolic (d-LVF) and systolic (s-LVF) functions were evaluated by echocardiography at baseline and after EX. Results: At baseline, cardiac geometry of R1 strain revealed normal, whereas P10 strain exhibited LV wall thinning and DD. The s-LVF of both strains was preserved. After EX, the body and heart weight of R1 mice were increased (BW; +6.7% and HW; +3.5% versus R1-ctl); however, EX had no influence on BW and HW of P10-strain. EX promoted LV hypertrophy in R1-EX, which was absent in P10-EX. The d-LVF of R1-EX was impaired but their s-LVF was unchanged. Vice versa, s-LVF of P10-EX turned impaired [EF (%) 68.9±1.5 versus 74.3±1.2 for P10-ctl], whereas the underlying DD of P10 was unaffected by EX. In C57-EX, cardiac function exhibited the similar trends observed in R1-EX. Cardiac Akt activity of R1-EX and C57-EX were enhanced compared to controls, which was diminished in P10-EX. Aged AktKO exhibited impaired s-LVF [EF (%) 61.3±1.0], nonetheless their DD remained unchanged [E/A=2.5±0.3, Dct (msec)= 35.0±2.4]. Conclusions: Our study demonstrates that #1 Akt is essential for adaptive response of s-LVF to EX and aging impairs Akt signaling in heart, leading to intolerance to EX, and #2 Akt is independent from modulation of cardiac DD induced by aging. Clinical implications are drawn that the benefit of EX on DD may be irrelevant to ameliorating myocardial property and a caution for monitoring cardiac geometry in aged patients is considered under prescribed EX as a palliative therapy for DD.