Ali Javaheri M.D., Ph.D. 

ABSTRACT

Doxorubicin (Dox) is a commonly used chemotherapeutic agent that has adverse effects on skeletal and cardiac muscle. Dox cardiotoxicity is initially characterized by skeletal and cardiac muscle atrophy and cardiac fibrosis. Dox-induced heart and skeletal muscle toxicity can progress to contractile dysfunction, sarcopenia, heart failure, and ultimately physical frailty – a phenotype of accelerated aging – and premature mortality. The immediate goal of this proposal is to determine how a range of dietary interventions can mitigate Dox toxicity and in so doing to identify biological mechanisms that can be therapeutically exploited. By understanding the mechanisms of accelerated aging and frailty, we can identify ways of intervening to mitigate the process. Accomplishing this objective will help us understand how to prevent physical frailty long-term. As an example, in a series of experiments published recently in Cell Metabolism, my laboratory discovered that sustained alternate-day fasting (ADF) in mice provokes Dox cardiotoxicity. In new studies in the first year of our Longer Life Foundation Program Award, we identified that Dox combined with ADF leads to the expansion of brown adipose tissue and increases in a secreted axonal guidance protein, SLIT2. By leveraging human samples from the Penn Heart Failure Study and aptamer proteomics, we identified that SLIT2 is the top biomarker that distinguishes Dox cardiomyopathy from other cardiomyopathies, and we have now further shown that SLIT2 is necessary and sufficient for Dox cardiotoxicity. This work, which was one specific aim of our proposal, is presently under consideration at Cell.

Having exploited our observation that fasting potentiates Dox toxicity to identify a novel biomarker and therapeutic (SLIT2), we currently propose to identify a dietary regimen that can mitigate Dox toxicity. In new preliminary studies, we randomized mice to standard high carbohydrate chow or a high protein, or high-fat diet. In these studies, we find that a high-fat diet mitigates Dox cardiotoxicity while a high-protein diet exacerbates it. These findings are surprising because a high-protein diet is currently considered the standard dietary approach to prevent muscle loss, albeit with limited scientific evidence for efficacy. Dox-treated mice fed a high-protein diet also exhibited reduced exercise capacity compared with Dox-treated mice fed a high-fat diet. In an analogous manner to what we have accomplished with fasting – namely, we used our fasting model to identify a translational disease mechanism and biomarker – we now propose to a) identify how high-fat feeding attenuates Dox cardiotoxicity, b) identify mechanisms of cardiac muscle toxicity induced by high protein intake, and c) evaluate the effect of a high protein diet on skeletal muscle mass and contractile function in Dox-treated mice.

Lay Summary:
Chemotherapy is a common treatment for cancer, but it can worsen other age-related health problems, such as heart disease, muscle loss, and weakness. In the first year of our Longer Life Foundation Award, we showed that intermittent fasting increases the side effects of chemotherapy in mice. This research has helped us identify potential new treatments to reduce these side effects. In the second and third years, we will study if other dietary approaches, like high-protein or high-fat diets, can change the side effects of chemotherapy. We will also explore new methods to help manage and reduce these side effects. These studies have enormous potential relevance not only to humans receiving chemotherapy but also to the selection of dietary macronutrients during aging and muscle loss.