Metabolite‐sensitive cross‐bridge models of human atria reveal the impact of diabetes on muscle mechanoenergetics

Abstract Type 2 diabetes is associated with a range of adverse health outcomes, including metabolic dysfunction and increased risk of heart failure. Although the interactions between diabetes and heart disease are complex and incompletely understood, they can be more effectively investigated using multiscale, biophysically based models of the underlying physiological processes. In this study, experimental data from non‐diabetic and diabetic human atrial muscles were used to develop metabolite‐sensitive cross‐bridge models representing each group. The parameterisation of these cross‐bridge models revealed that reduced muscle stress development and a leftward shift of the complex modulus measured in the diabetic muscles could be attributed to reduced cross‐bridge stiffness and slower cross‐bridge detachment rates, respectively. These cross‐bridge models were also integrated into muscle models to investigate the effects of diabetic cross‐bridge function, Ca 2+ handling and altered metabolite availability on isometric and physiological work‐loop contractions. The diabetic model produced isometric twitches with lower amplitude and prolonged duration and, in response to lowered ATP concentration, the diastolic stress increased notably. In work‐loop simulations, the diabetic model exhibited slower shortening, reduced work output and lower power of shortening. However, it was also more efficient and had a less pronounced negative response to increases in P i concentration. These simulations demonstrate that while experimentally measured differences in diabetic cardiac tissues can lead to impaired function during physiological contractions, they may also offer compensatory advantages. The insights of this study offer clear mechanisms of mechanoenergetic dysfunction in diabetic heart muscle, identifying potential therapeutic targets to improve cardiac outcomes for individuals with diabetes. image Key points We used multiscale mathematical models to investigate the interaction between mechanical and energetic systems in diabetic cardiomyopathy. Using previously collected data from human atrial tissues, we developed models of non‐diabetic and diabetic cross‐bridge function. The models confirmed that the mechanisms underlying slower cycling and lower force production in the diabetic tissues were slower cross‐bridge detachment rates and lower cross‐bridge stiffness. Integrating into muscle models and predicting the behaviour under different types of contraction revealed that these differences lead to longer force twitches with lower amplitude, less work done, slower shortening and lower power generation in the diabetic muscles. This modelling study presents novel human atrial cross‐bridge models and offers clear mechanisms of mechanical and energetic dysfunction in diabetic heart muscle with potential pathways for treatment.