High‐Protein Diet Ameliorates Cardiomyopathy in a Cardiac‐Specific AGL Knockout Mouse Model: Association With Upregulated Hepatic Gluconeogenesis

ABSTRACT

Glycogen storage disease type IIIa (GSDIIIa) causes progressive cardiomyopathy, and current high‐fat dietary strategies lack consensus regarding long‐term cardiovascular safety. We evaluated the efficacy and safety of high‐protein versus high‐fat diets in a novel cardiac‐specific AGL knockout (CKO; AGL ^flox/flox / MHC‐Cre ) mouse model to specifically assess isolated cardiac responses. CKO mice were randomized at weaning to High‐Protein (HPD), High‐Protein High‐Fat (HPHFD), or Low‐Protein (LPD) diets, with approximate protein/fat/carbohydrate distributions of 40%/4%/50%, 40%/50%/10%, and 10%/4%/80%, respectively; CKO mice on normal diet (ND) and AGL ^flox/flox mice served as controls. Cardiac phenotypes and hepatic gluconeogenic enzymes were evaluated longitudinally up to 24 weeks. CKO‐ND mice developed progressive cardiomyopathy with elevated myocardial glycogen at 24 weeks (32.01 ± 3.22 vs. 5.90 ± 2.21 mg/g in controls, p  < 0.001), reduced left ventricular ejection fraction, and elevated serum creatine kinase. Both HPD and HPHFD significantly reduced myocardial glycogen burden (12.82 ± 3.58 and 15.07 ± 4.40 mg/g, p  < 0.001), restored systolic function, and normalized hypertrophy. However, HPHFD induced distinct hyperlipidemia, whereas HPD maintained a stable lipid profile. Furthermore, therapeutic benefits in high‐protein groups were associated with upregulated hepatic rate‐limiting gluconeogenic enzymes (FBP2, PCK1). In this cardiac‐specific AGL knockout model, a high‐protein, non‐high‐fat diet attenuated cardiac glycogen accumulation and systolic dysfunction without the hyperlipidemia observed with the high‐fat regimen. These preclinical findings support further evaluation of high‐protein dietary strategies for GSDIIIa cardiomyopathy and suggest a possible liver‐heart metabolic axis involving hepatic gluconeogenesis.