Introduction: Type 2 diabetes (T2D) and obesity reduce healthspan in part by increasing risk of cardiovascular events including arrhythmias, heart attacks, cardiomyopathies, and coronary heart disease. Low protein diets and specific amino acid deficiencies, such as dietary methionine, have been observed to reduce body weight, improve glycemic control, and ultimately extend lifespan. However, little is known of how systemic protein deficiency may alter myocardial integrity and bioenergetic function.

Methods: Twelve-month-old male C57BL/6J mice were randomized to a normal protein (NP; 20% casein), low protein (LP; 5% casein), high fat (HF; 60% fat), or high fat + low protein (HF + LP; 60% fat, 5% casein) diet for 16 weeks. Body weight was measured weekly. Oxidative phosphorylation (OXPHOS) and electron transport system (ETS) capacity was determined in permeabilized myocardial fiber bundles by high-resolution respirometry. Citrate synthase activity was determined by kinetic enzymatic assay. Cardiomyocyte diameter was determined by haemotoxylin and eosin (H&E) staining. Untargeted transcriptomic profiling was conducted by RNA sequencing. Changes in protein expression were determined by immunoblotting.

Results: LP reduced body weight relative to NP and HF, whereas HF+LP reduced body weight relative to HF, but was greater than LP alone. LP and LP+HF increased heart weight relative to body weight and cardiomyocyte diameter relative to both NP and HF. Succinate linked OXPHOS and ETS (complex II coupled and uncoupled) was reduced in both LP and LP+HF compared to NP and HF alone.

Conclusion: Protein restriction reduces cardiac OXPHOS capacity and induces cardiomyocyte hypertrophy in aging mice. These results question the applicability of chronic protein restriction for management of obesity-related diseases. Further investigation is required to determine if the alterations in cardiac bioenergetic function and structure are advantageous or maladaptive responses.


C.L. Axelrod: None. W.S. Dantas: None. G. Davuluri: None. W.T. King: None. C.M. Hill: None. C. Morrison: None. J.P. Kirwan: None.


National Institute of Diabetes and Digestive and Kidney Diseases (DK105032); National Institute of General Medical Sciences (GM104940)

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