Supplementing Soy-Based Diet with Creatine in Rats: Implications for Cardiac Cell Signaling and Response to Doxorubicin

Laurence Kay,Stéphane Attia,Piero Sestili,Christian Zuppinger,Theo Wallimann,Lucia Potenza,Malgorzata Tokarska-Schlattner,Cindy Tellier,Cinzia Calcabrini,Hubert Roth,Uwe Schlattner,Isabelle Hininger-Favier

doi:10.3390/nu14030583

Abstract

Nutritional habits can have a significant impact on cardiovascular health and disease. This may also apply to cardiotoxicity caused as a frequent side effect of chemotherapeutic drugs, such as doxorubicin (DXR). The aim of this work was to analyze if diet, in particular creatine (Cr) supplementation, can modulate cardiac biochemical (energy status, oxidative damage and antioxidant capacity, DNA integrity, cell signaling) and functional parameters at baseline and upon DXR treatment. Here, male Wistar rats were fed for 4 weeks with either standard rodent diet (NORMAL), soy-based diet (SOY), or Cr-supplemented soy-based diet (SOY + Cr). Hearts were either freeze-clamped in situ or following ex vivo Langendorff perfusion without or with 25 μM DXR and after recording cardiac function. The diets had distinct cardiac effects. Soy-based diet (SOY vs. NORMAL) did not alter cardiac performance but increased phosphorylation of acetyl-CoA carboxylase (ACC), indicating activation of rather pro-catabolic AMP-activated protein kinase (AMPK) signaling, consistent with increased ADP/ATP ratios and lower lipid peroxidation. Creatine addition to the soy-based diet (SOY + Cr vs. SOY) slightly increased left ventricular developed pressure (LVDP) and contractility dp/dt, as measured at baseline in perfused heart, and resulted in activation of the rather pro-anabolic protein kinases Akt and ERK. Challenging perfused heart with DXR, as analyzed across all nutritional regimens, deteriorated most cardiac functional parameters and also altered activation of the AMPK, ERK, and Akt signaling pathways. Despite partial reprogramming of cell signaling and metabolism in the rat heart, diet did not modify the functional response to supraclinical DXR concentrations in the used acute cardiotoxicity model. However, the long-term effect of these diets on cardiac sensitivity to chronic and clinically relevant DXR doses remains to be established.

Highlights

Nutritional habits are increasingly recognized for their impact on cardiovascular health and disease, including prevention of cancer relapse or different comorbidities [1]
This is of particular interest for acute or chronic cardiotoxicity caused by anticancer chemotherapeutics, in particular anthracyclines, such as doxorubicin (DXR; reviewed in [2,3,4]), for which efficient preventive or therapeutic strategies are still lacking
The effects of the three nutritional regimens, standard rodent chow (NORMAL), soybased diet (SOY), and Cr-supplemented soy-based diet (SOY + Cr), on the heart under control and DXR-challenged conditions were studied in a rat model (Figure 1)

Summary

Introduction

Nutritional habits are increasingly recognized for their impact on cardiovascular health and disease, including prevention of cancer relapse or different comorbidities [1]. This is of particular interest for acute or chronic cardiotoxicity caused by anticancer chemotherapeutics, in particular anthracyclines, such as doxorubicin (DXR; reviewed in [2,3,4]), for which efficient preventive or therapeutic strategies are still lacking. Cr and PCr, together with isoforms of creatine kinase (CK), confer bioenergetic advantages by providing an efficient energy buffer and transfer system for cells and tissues with high and fluctuating energy requirements, such as the heart [17]. Cr and PCr interact with anionic membrane phospholipids, increasing phospholipid packing and stabilizing and protecting biomembranes [26]

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