Thermoneutrality Reveals True Cardiac Adaptations to Exercise, Disease, and Aging in Male Mice

AIM: Standard laboratory housing (21°C) imposes chronic cold stress on mice, yet its fundamental impact on cardiac plasticity remains poorly defined. We systematically interrogated how environmental temperature dictates cardiac responses to endurance exercise, doxorubicin (DOX)-induced cardiotoxicity, and aging. METHODS: Male mice were housed at standard room temperature (RT) or thermoneutrality (30°C, TN) and subjected to exercise, detraining, DOX treatment, or natural aging. Cardiac remodeling was evaluated by integrating physiological phenotyping (echocardiography, body composition) with comprehensive transcriptomic and proteomic profiling. RESULTS: Housing temperature fundamentally alters cardiac molecular baselines and adaptive trajectories. Exercise at TN elicited a coordinated, extracellular matrix (ECM)-focused transcriptional program, improving contractile function without inducing overt hypertrophy. Conversely, RT triggered a broad, uncoordinated stress response. Notably, while RT permitted classic regression of exercise-induced hypertrophy, detraining at TN revealed a unique cardiac structural economy, where cardiac mass significantly dropped below sedentary controls while maintaining enhanced functional efficiency. In pathological models, RT-induced compensatory survival pathways masked the true structural severity of DOX cardiotoxicity and paradoxically buffered against fibrosis. Furthermore, RT exacerbated cardiac aging phenotypes, inducing widespread fibrosis and upregulating senescence markers and specific microRNAs that remained quiescent under TN. CONCLUSION: Environmental temperature profoundly reshapes cardiac adaptive plasticity. The chronic thermal stress of standard housing distorts intrinsic molecular signaling, highlighting thermoneutrality as a crucial baseline for revealing true physiological adaptations and ensuring the translational validity of cardiovascular models.