Creatine supplementation and respiratory muscle function in health and disease: translational insights from human to mouse

Background Respiratory muscle weakness contributes to exercise intolerance in both ageing and disease; however current treatment options remain limited. In this study, we investigated the potential for creatine (Cr) supplementation to increase inspiratory muscle strength (PImax) in health and mitigate diaphragm dysfunction in disease. Methods Using a translational approach, we combined a human inspiratory muscle training (IMT) intervention with a mechanistic preclinical heart failure (HF) model. Twenty-nine healthy males (FEV 1 >80% pred) completed 4 weeks of IMT (30-breaths, twice daily, at 50% PImax), either alone (IMT: n=15) or with Cr (IMT+Cr: n=14). PImax and expiratory muscle strength (PEmax) were assessed pre- and post-IMT. Subsequently, isolated diaphragm fibre bundles from healthy and post-myocardial infarction HF mice underwent in vitro analysis following 3 weeks of Cr supplementation or placebo. Results In humans, baseline PImax was similar between groups (p=0.554). The 33% increase in PImax after IMT+Cr was greater than the 18% increase after IMT (condition×time interaction: p=0.031). In mice, Cr had no effect in health but increased diaphragm function in HF with improvements in specific force, twitch relaxation, and fatigue resistance (all p<0.05). Conclusion Cr supplementation was associated with a greater increase in PImax following IMT in healthy adults and improved diaphragm contractile performance in a preclinical model of HF. These findings provide biological plausibility for a potential effect of Cr on intrinsic diaphragm function and warrant confirmation in adequately powered, randomised controlled trials.