["The Journal of Physiology, Volume 604, Issue 13, Page 5316-5341, 1 July 2026. ", "\nAbstract figure legend In this study, we used mathematical modelling to explore the effect of diabetes on muscle mechanoenergetics. Our parameterisation of cross‐bridge models using data from non‐diabetic and diabetic human atrial tissues revealed lower values for cross‐bridge stiffness, detachment rates, attachment rates and lower ATP sensitivity in diabetes. Simulations of muscle level function showed that diabetes reduced the amplitude and duration of isometric twitches and reduced work, velocity and power, but increased cross‐bridge efficiency, in work‐loop contractions.\n\n\n\n\n\n\n\n\n\nAbstract\nType 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, Ca2+ 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 Pi 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.\n\n\n\n\n\n\n\n\n\nKey points\n\nWe used multiscale mathematical models to investigate the interaction between mechanical and energetic systems in diabetic cardiomyopathy.\nUsing 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.\nIntegrating 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.\nThis 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.\n\n\n"]