High-protein diet preserved LV mass and function, reduced cardiomyocyte atrophy, and improved survival in anthracycline-treated mice despite persistent mitochondrial dysfunction.
Does a high-protein diet mitigate anthracycline-induced cardiac atrophy and functional deterioration in a preclinical mouse model?
A high-protein diet preserves LV mass and function and improves survival in a mouse model of anthracycline-induced cardiotoxicity, highlighting its potential as a complementary cardioprotective strategy.
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Abstract Background Anthracycline-induced cardiotoxicity (AIC) frequently manifests initially with myocardial atrophy, a reduction in cardiac mass that precedes functional decline and heart failure. High-protein diet (HPD) has been shown to prevent muscle atrophy in other conditions, but has not been tested before in the context of AIC. Purpose To evaluate whether a HPD mitigates anthracycline-induced cardiac atrophy and functional deterioration in a preclinical mouse model of AIC. Methods Young male CD1 mice (6 weeks old) were randomized to receive either a chow diet (22% protein) or HPD (45.9% protein) for four weeks before and throughout doxorubicin (DOX) treatment. DOX was administered (5 mg/kg/week, i.p.) for five weeks (cumulative dose: 25 mg/kg). Echocardiography was conducted at baseline and at multiple time points post-DOX (weeks 1, 9, and 15) to monitor LV function and mass. Additional analyses included proteomics, immunohistochemistry, biochemical markers of cardiac injury, and assays to evaluate the contractile state and actin-myosin interaction efficiency (mant-ATP assay), mitochondrial function (high-resolution respirometry), and ultrastructure (transmission electron microscopy). Results Following DOX treatment, HPD-fed mice exhibited improved survival and preserved cardiac function, as indicated by higher LV mass and LVEF compared to chow-fed animals. Histological analysis confirmed reduced cardiomyocyte atrophy, with an increased cross-sectional area in HPD-treated mice. At the molecular level, proteomic analysis demonstrated enhanced protein biosynthesis, with upregulation of ribosomal subunits counteracting the DOX-induced protein turnover imbalance. Furthermore, HPD preserved sarcomeric function, as reflected by lower energy-consuming disordered-relaxed state (DRX) levels in mant-ATP assays compared to chow-fed animals. However, mitochondrial function remained impaired, as shown by reduced respiratory capacity in high-resolution respirometry and structural abnormalities observed in transmission electron microscopy analysis. Conclusions A HPD prevents key manifestations of AIC, preserving LV mass and function while supporting protein homeostasis. Furthermore, HPD is associated with significantly less AIC-associated mortality. Mitochondrial dysfunction is not rescued by HPD, suggesting that its benefits are related to a sarcomere effect. These findings underscore the potential of HPD as a complementary, non-invasive strategy to enhance cardiac protection, particularly when combined with interventions targeting mitochondrial health.
Priego et al. (Sat,) reported a other. High-protein diet preserved LV mass and function, reduced cardiomyocyte atrophy, and improved survival in anthracycline-treated mice despite persistent mitochondrial dysfunction.