Cardiomyocyte Atrophy, an Underestimated Contributor in Doxorubicin-Induced Cardiotoxicity

Abstract

Left ventricular (LV) mass loss is prevalent in doxorubicin (DOX)-induced cardiotoxicity and is responsible for the progressive decline of cardiac function. Comparing with the well-studied role of cell death, the part of cardiomyocyte atrophy (CMA) playing in the LV mass loss is underestimated and the knowledge of the underlying mechanism is still limited. In this review, we summarized the recent advances in the DOX-induced CMA. We found that the CMA caused by DOX is associated with the upregulation of FOXOs and “atrogenes,” the activation of transient receptor potential canonical 3-NADPH oxidase 2 (TRPC3-Nox2) axis, and the suppression of IGF-1-PI3K signaling pathway. The imbalance of anabolic and catabolic process may be the common final pathway of these mechanisms. At last, we provided some strategies that have been demonstrated to alleviate the DOX-induced CMA in animal models.

Anthracycline Cardiotoxicity Induces Progressive Changes in Myocardial Metabolism and Mitochondrial Quality Control

“…The early disease stage after doxorubicin treatment, when cardiac function was still preserved, was characterized by reductions in LV mass detected by echocardiography, heart weight, and cardiomyocyte area. A decrease in cardiac mass after doxorubicin exposure has been reported previously in clinical trials 15 , 16 and in mouse models. 17 Although the mechanism of cardiomyocyte atrophy after doxorubicin exposure is poorly understood, there is evidence that it could be mediated by activation of cyclin-dependent kinase 2 (CDK2)–dependent forkhead box protein O1 (FOXO1).…”

“…These findings suggest that interventions targeting early doxorubicin-induced cardiomyocyte atrophy could represent a therapeutic benefit in AIC. One possible approach to alleviating cardiac atrophy is increased physical activity, 15 and benefits might also be obtained with specific nutritional approaches such as high-protein or high-calorie diets, as caloric restriction is known to induce LV atrophy. 19 The progression in our model from early cardiac atrophy to deteriorating cardiac function at the intermediate and advanced AIC stages parallels observations in anthracycline-treated cancer survivors.…”

Exposure to Doxorubicin Modulates the Cardiac Response to Isoproterenol in Male and Female Mice

“…DOX-induced cardiac atrophy may be mediated by multiple mechanisms including p53-dependent inhibition of mammalian target of rapamycin (mTOR) [ 30 ] and forkhead box O1 (FOXO1)-mediated activation of muscle RING finger 1 (MuRF1) [ 31 ]. Additional pathways have been suggested to mediate DOX-induced cardiac atrophy including impaired insulin-like growth factor 1 (IGF-1) signaling, reactive oxygen species (ROS)-dependent upregulation of NADPH oxidase 2 (Nox2), altered PI3K-AKT pathway, and activated p38 MAPK (reviewed in [ 32 , 33 ]). Female mice were protected from DOX-induced cardiac atrophy and demonstrated a robust hypertrophic response to the ISO challenge.…”

Impaired end joining induces cardiac atrophy in a Hutchinson–Gilford progeria mouse model

“…Consistent with our study, mice with deficiency in NHEJ exhibited cardiomyopathies ( 70 , 71 ). Moreover, a number of chemotherapeutic agents that function by inducing DNA damage, such as doxorubicin, have also been reported to cause cardiac atrophy in both patients and animal models ( 72 – 75 ). The mechanistic link between DNA damage response and the cardiomyopathy we identified might help explain the age-related changes in the heart in both animal models and humans.…”