This study developed an approach to quantify frailty with a frailty index (FI) and investigated whether age-related changes in contractions, calcium transients, and ventricular myocyte length were more prominent in mice with a high FI. The FI combined 31 variables that reflect different aspects of health in middle-aged (∼12 months) and aged (∼30 months) mice of both sexes. Aged animals had a higher FI than younger animals (FI = 0.43 ± 0.03 vs 0.08 ± 0.02, p < .001, n = 12). Myocyte hypertrophy increased by 30%-50% as the FI increased in aged animals. Peak contractions decreased more than threefold from lowest to highest FI values in aged mice (p < .037), but calcium transients were unaffected. Similar results were seen with an FI based on eight noninvasive variables identified as underlying factors. These results show that an FI can be developed for murine models and suggest that age-associated changes in myocytes are more prominent in animals with a high FI.

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This study established conditions to induce regular estrous cycles in female C57BL/6J mice and investigated the impact of the estrous cycle on contractions, Ca2+ transients, and underlying cardiac excitation-contraction (EC)-coupling mechanisms. Daily vaginal smears from group-housed virgin female mice were stained to distinguish estrous stage (proestrus, estrus, metestrus, diestrus). Ventricular myocytes were isolated from anesthetized mice. Contractions and Ca2+ transients were measured simultaneously (4 Hz, 37 °C). Interestingly, mice did not exhibit regular cycles unless they were exposed to male pheromones in bedding added to their cages. Field-stimulated myocytes from mice in estrus had larger contractions (∼2-fold increase), larger Ca2+ transients (∼1.11-fold increase), and longer action potentials (>2-fold increase) compared with other stages. Larger contractions and Ca2+ transients were not observed in estrus myocytes voltage-clamped with shorter action potentials. Voltage-clamp experiments also demonstrated that estrous stage had no effect on Ca2+ current, EC-coupling gain, diastolic Ca2+, sarcoplasmic reticulum (SR) Ca2+ content, or fractional release. Although contractions were largest in estrus, myofilament Ca2+ sensitivity was lowest (EC50 values ∼1.15-fold higher) in conjunction with increased phosphorylation of myosin binding protein C in estrus. Contractions were enhanced in ventricular myocytes from mice in estrus because action potential prolongation increased SR Ca2+ release. These findings demonstrate that cyclical changes in reproductive hormones associated with the estrous cycle can influence myocardial electrical and contractile function and modify Ca2+ homeostasis. However, such changes are unlikely to occur in female mice housed in groups under conventional conditions, since these mice do not exhibit regular estrous cycles.

We investigated myocardial effects of acute application of progesterone. In females, but not males, progesterone attenuates and slows cardiomyocyte contraction with no effect on calcium transients. Progesterone also reduces myofilament calcium sensitivity in female hearts. This may adversely affect heart function, especially when serum progesterone levels are high in pregnancy.Listen to this article's corresponding podcast at https://ajpheart.podbean.com/e/acute-progesterone-modifies-cardiac-contraction/.