Long-term testosterone deficiency modifies myofilament and calcium-handling proteins and promotes diastolic dysfunction in the aging mouse heart.

The impact of long-term gonadectomy (GDX) on cardiac contractile function was explored in the setting of aging. Male mice were subjected to bilateral GDX or sham operation (4 wk) and investigated at 16-18 mo of age. Ventricular myocytes were field stimulated (2 Hz, 37°C). Peak Ca2+ transients (fura 2) and contractions were similar in GDX and sham-operated mice, although Ca2+ transients (50% decay time: 45.2 ± 2.3 vs. 55.6 ± 3.1 ms, P < 0.05) and contractions (time constant of relaxation: 39.1 ± 3.2 vs. 69.5 ± 9.3 ms, P < 0.05) were prolonged in GDX mice. Action potential duration was increased in myocytes from GDX mice, but this did not account for prolonged responses, as Ca2+ transient decay was slow even when cells from GDX mice were voltage clamped with simulated "sham" action potentials. Western blots of proteins involved in Ca2+ sequestration and efflux showed that Na+/Ca2+ exchanger and sarco(endo)plasmic reticulum Ca2+-ATPase type 2 protein levels were unaffected, whereas phospholamban was dramatically higher in ventricles from aging GDX mice (0.24 ± 0.02 vs. 0.86 ± 0.13, P < 0.05). Myofilament Ca2+ sensitivity at physiological Ca2+ was similar, but phosphorylation of essential myosin light chain 1 was reduced by ≈50% in ventricles from aging GDX mice. M-mode echocardiography showed no change in systolic function (e.g., ejection fraction). Critically, pulse-wave Doppler echocardiography showed that GDX slowed isovolumic relaxation time (12.9 ± 0.9 vs. 16.9 ± 1.0 ms, P < 0.05), indicative of diastolic dysfunction. Thus, dysregulation of intracellular Ca2+ and myofilament dysfunction contribute to deficits in contraction in hearts from testosterone-deficient aging mice. This suggests that low testosterone helps promote diastolic dysfunction in the aging heart. NEW & NOTEWORTHY The influence of long-term gonadectomy on contractile function was examined in aging male hearts. Gonadectomy slowed the decay of Ca2+ transients and contractions in ventricular myocytes and slowed isovolumic relaxation time, demonstrating diastolic dysfunction. Underlying mechanisms included Ca2+ dysregulation, elevated phospholamban protein levels, and hypophosphorylation of a myofilament protein, essential myosin light chain. Testosterone deficiency led to intracellular Ca2+ dysregulation and myofilament dysfunction, which may facilitate diastolic dysfunction in the setting of aging.

Implementation of the mouse frailty index.

Frailty is considered a state of high vulnerability for adverse health outcomes for people of the same age. Those who are frail have higher mortality, worse health outcomes, and use more health care services than those who are not frail. Despite this, little is known about the biology of frailty, the effect of frailty on pharmacological or surgical outcomes, and potential interventions to attenuate frailty. In humans, frailty can be quantified using a frailty index (FI) based on the principle of deficit accumulation. The recent development of an FI in naturally ageing mice provides an opportunity to conduct frailty research in a validated preclinical model. The mouse FI has been successfully used across a wide range of applications; however, there are some factors that should be considered in implementing this tool. This review summarises the current literature, presents some original data, and suggests areas for future research on the current applications of the mouse FI, inter-rater reliability of the FI, the effect of observer characteristics and environmental factors on mouse FI scores, and the individual items that make up the FI assessment. The implementation of this tool into preclinical frailty research should greatly accelerate translational research in this important field.

Testosterone modulates cardiac contraction and calcium homeostasis: cellular and molecular mechanisms.

The incidence of cardiovascular disease rises dramatically with age in both men and women. Because a woman's risk of cardiovascular disease rises markedly after the onset of menopause, there has been growing interest in the effect of estrogen on the heart and its role in the pathophysiology of these diseases. Much less attention has been paid to the impact of testosterone on the heart, even though the levels of testosterone also decline with age and low-testosterone levels are linked to the development of cardiovascular diseases. The knowledge that receptors for all major sex steroid hormones, including testosterone, are present on individual cardiomyocytes suggests that these hormones may influence the heart at the cellular level. Indeed, it is well established that there are male-female differences in intracellular Ca(2+) release and contraction in isolated ventricular myocytes. Growing evidence suggests that these differences arise from effects of sex steroid hormones on processes involved in intracellular Ca(2+) homeostasis. This review considers how myocardial contractile function is modified by testosterone, with a focus on the impact of testosterone on processes that regulate Ca(2+) handling at the level of the ventricular myocyte. The idea that testosterone regulates Ca(2+) handling in the heart is important, as Ca(2+) dysregulation plays a key role in the pathogenesis of a variety of different cardiovascular diseases. A better understanding of sex hormone regulation of myocardial Ca(2+) homeostasis may reveal new targets for the treatment of cardiovascular diseases in all older adults.