Decline of cardiomyocyte contractile performance and bioenergetic function in socially stressed male rats

Abstract

Chronic social stress has been epidemiologically linked to increased risk for cardiovascular disease, yet the underlying pathophysiological mechanisms are still largely elusive. Mitochondrial (dys)function represents a potential intersection point between social stress exposure and (mal)adaptive cardiac responses. In this study, we used a rodent model of social stress to study the extent to which alterations in the cellular mechanical properties of the heart were associated with changes in indexes of mitochondrial function. Male adult rats were exposed to repeated episodes of social defeat stress or left undisturbed (controls). ECG signals were recorded during and after social defeat stress. Twenty-four hours after the last social defeat, cardiomyocytes were isolated for analyses of mechanical properties and intracellular Ca²⁺ dynamics, mitochondrial respiration, and ATP content. Results indicated that social defeat stress induced potent cardiac sympathetic activation that lasted well beyond stress exposure. Moreover, cardiomyocytes of stressed rats showed poor contractile performance (e.g., slower contraction and relaxation rates) and intracellular Ca²⁺ derangement (e.g., slower Ca²⁺ clearing), which were associated with indexes of reduced reserve respiratory capacity and decreased ATP production. In conclusion, this study suggests that repeated social stress provokes impaired cardiomyocyte contractile performance and signs of altered mitochondrial bioenergetics in the rat heart. Future studies are needed to clarify the causal link between cardiac and mitochondrial functional remodeling under conditions of chronic social stress.

Keywords: ATP; Cardiomyocyte; Heart rate; Intracellular calcium dynamics; Mitochondria; Social stress.

Figure 1

Effects of repeated social defeat stress on cardiomyocyte mechanics. (A) Representative traces of sarcomere shortening in cells obtained from control (CTR) and repeated social defeat (RSD) rats. The histograms (panels B–E) report the maximal rate of shortening (-dl/dt_max), maximal rate of relengthening (+dl/dt_max), fraction of shortening (FS), and time of total cycle (T-cycle) measured at 10%, 50%, and 90% of relengthening CTR (n = 5; 136 cells) and RSD (n = 5; 127 cells) rats. Data are reported as means ± SEM. ∗∗p < 0.01.

Figure 2

Effects of repeated social defeat stress on calcium transients. (A) Representative traces of calcium transients in cardiomyocytes from control (CTR) and repeated social defeat (RSD) rats. The histograms (panels B–D) report the amplitude of the calcium transient expressed as fluorescence peak normalized to baseline (f/f0), the time constant of intracellular Ca²⁺ decay (τ), and the time-to-peak of the calcium transient (TTP) in CTR (n = 5; 80 cells) and RSD (n = 5; 86 cells) rats. Data are reported as means ± SEM. ∗∗p < 0.01.

Figure 3

Effects of repeated social defeat stress on mitochondrial respiration and ATP content. The histograms report the basal rate of oxygen consumption (coupled respiration) (A), the maximal rate of oxygen consumption in the presence of the uncoupler Carbonyl cyanide m-chlorophenylhydrazone (CCCP; uncoupled respiration) (B), the ratio between uncoupled and coupled respiration as index of normalized respiratory reserve capacity (C), the difference between uncoupled and coupled respiration as index of respiratory reserve capacity (D), and ATP content (E) in cardiomyocytes from control (CTR) and repeated social defeat (RSD) rats (n = 5 per group). Data are reported as means ± SEM. ∗p < 0.05.

Figure 4

Correlations between indexes of reserve respiratory capacity (the ratio (panel A) and the difference (panel B) between uncoupled and coupled respiration, respectively) and ATP content in CTR (n = 5) and RSD (n = 5) rats.