Effects of Short-Term Treadmill Exercise Training or Growth Hormone Supplementation on Diastolic Function and Exercise Tolerance in Old Rats

BOTH diastolic function and exercise tolerance decline in the course of normal aging (1,2). Diastolic dysfunction is characterized by incomplete relaxation of the ventricle and increased ventricular stiffness, impairing early and late filling, respectively (3). Although older patients with primary diastolic dysfunction may be asymptomatic at rest, this age-related cardiac phenotype often becomes apparent with exercise. Specifically, patients with diastolic dysfunction are not able to augment left ventricular (LV) filling appropriately with the tachycardia accompanying exercise, unless left atrial pressures are excessively increased (4). This type of exercise intolerance, in part, defines diastolic heart failure (DHF) (5), the most common form of heart failure (HF) in older patients. Exercise intolerance among HF patients with diastolic dysfunction is as severe as that among age-matched HF patients with severe systolic dysfunction (6), and this impairs quality of life. Multiple lines of data from aging humans and animals suggest that aerobic exercise training may improve diastolic function and exercise tolerance (7-13). Although the mechanisms underlying this exercise-induced benefit are unclear, studies have shown that long-term exercise training in senescent rats increases sarcoplasmic reticular (SR) Ca2+ uptake (13,14) and attenuates age-associated changes in collagen deposition (15), two factors known to influence LV relaxation and stiffness, respectively (3). However, given the integral effects of exercise on cardiovascular structure and function (16-20), additional molecular mechanisms and signaling pathways through which exercise enhances diastolic function in the elderly population remain to be explored. One age-related physiologic change that may be partially responsible for diastolic dysfunction and exercise intolerance is a decline in the pulsatility of growth hormone (GH) and its circulating local effector, insulin-like growth factor-1 (IGF-1). Although GH and IGF-1 are involved in heart development and in maintaining cardiac structure and performance (21), clinical and experimental evidence (21-27), including results from our laboratory (28), indicate that age-related reductions in the GH/IGF-1 axis are also associated with diastolic dysfunction, HF, and reduced exercise performance. Furthermore, we previously demonstrated that long-term GH replacement in aged rats increases circulating IGF-1 and attenuates diastolic dysfunction and LV remodeling, in part via a reduction in cardiac angiotensin II (Ang II) (28). Because another stimulus of the GH/IGF-1 axis is physical exercise (29,30), the mechanisms that underlie the lusitropic potential of habitual exercise training and GH/IGF-1 may be interrelated, and this is the focus of our study. To date, no study has compared the influence of short-term exercise training on IGF-1 production and diastolic function in aged and mature adult rats. Brown Norway × Fisher 344 (BNF344) male rats were specifically chosen for the present study, because these animals display mild diastolic dysfunction and a reduction in GH and IGF-1 production as they age (28,31), without overt cardiovascular disease. These changes are similar to changes that occur in healthy persons >60 years of age (32,33). We also investigated the interactions between the GH/IGF-1 axis and exercise training with respect to the expression of sarcoplasmic Ca2+ adenosine triphosphatase (SERCA2). We hypothesized that brief exercise training (4 weeks) during old age would attenuate age-induced down-regulation of IGF-1, and that improved IGF-1 signaling would lead to an increase in the SR calcium regulatory protein, SERCA2, suggesting another mechanism by which exercise training limits cardiac aging. We also evaluated the role of cardiac angiotensin peptides with respect to aging, exercise, and GH, because activation of the renin angiotensin system (RAS) has been implicated in the pathogenesis of diastolic heart disease (34) and has been linked to GH/IGF-1 (28). To the best of our knowledge, this is the first study to investigate the effect of short-term exercise or GH replacement, late in life, on diastolic function of “healthy” aging rats.