Ali Javaheri M.D., Ph.D.
FINAL REPORT
Chemotherapy remains one of the most effective treatments for cancer, yet its benefits are frequently accompanied by systemic toxicities that extend beyond tumor tissue. Among these, skeletal and cardiac muscle loss are increasingly recognized as major determinants of morbidity, treatment intolerance, and long-term functional decline. Anthracyclines such as doxorubicin are well known to cause cardiotoxicity, but they also induce a broader catabolic state characterized by muscle atrophy, altered substrate utilization, and impaired regenerative capacity. These effects are particularly consequential in older individuals, in whom baseline muscle mass and metabolic flexibility are already diminished.
Muscle loss during cancer therapy intersects biologically with aging. Both processes involve dysregulated nutrient sensing, mitochondrial stress, inflammatory signaling, and impaired proteostasis. As lifespan increases and more patients survive cancer into older age, preventing therapy-induced muscle decline has become central not only to oncology outcomes but also to long-term healthspan. Interventions that modulate metabolism, such as fasting, macronutrient manipulation, or pharmacologic targeting of nutrient-sensing pathways, are increasingly promoted to mitigate chemotherapy toxicity, yet their effects on cardiac and skeletal muscle remain incompletely defined.
In this context, our project examined whether dietary interventions could modify doxorubicin-induced muscle atrophy and cardiac remodeling. We found that intermittent fasting induced marked adipose tissue remodeling that unexpectedly accelerated cardiac wasting in the setting of doxorubicin exposure. Rather than protecting against chemotherapy-associated muscle loss, fasting altered systemic metabolic signaling, thereby amplifying cardiomyocyte atrophy. In contrast, a high-fat diet prevented doxorubicin-induced cardiac muscle atrophy and preserved cardiomyocyte size under stress conditions. Mechanistic studies identified lysosomal lipolysis as a critical regulator of cardiomyocyte growth and survival, a pathway not previously recognized as central to chemotherapy-associated cardiac wasting. Unexpectedly, high protein feeding failed to rescue cardiac muscle mass and, in some settings, exacerbated atrophy, refining prevailing assumptions regarding protein supplementation during catabolic stress.
Although the original proposal focused on chemotherapy-associated muscle loss, this line of investigation ultimately led to the downstream identification of a novel therapeutic strategy that prevents muscle loss in the broader context of weight reduction. This discovery extends beyond anthracycline cardiotoxicity and has potential implications for aging-associated sarcopenia, obesity treatment, and intentional weight loss. Further translational development and grant submissions are in progress. Specific molecular components and therapeutic details are withheld pending intellectual property protection and considerations.
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.