Effect of age on the development of acute Doxorubicin-induced respiratory muscle dysfunction

Doxorubicin (DOX) is a highly effective antitumor agent utilized for the treatment of both pediatric and adult cancers. Despite its clinical efficacy, systemic DOX treatment can lead to respiratory muscle dysfunction due to its off-target accumulation within muscle tissue. In fact, the diaphragm is particularly susceptible to DOX toxicity, with diaphragm weakness a key contributor to patient fatigue, reduced quality of life and increased mortality. While the factors that affect patient’s susceptibility to DOX respiratory toxicity are unclear, age is hypothesized to be a major biological variable that impacts how tissues respond to chemotherapeutic stress due to differences in hormone levels, body composition and the rate of drug clearance. Nevertheless, the age-dependent physiological effects of DOX on respiratory function remain under explored. Therefore, the goal of this study was to assess the acute physiological effects of DOX treatment on respiratory muscle function across different age groups. To represent pediatric and adult populations, 2- and 20-month-old female Sprague-Dawley rats were utilized for these experiments. Whole-body plethysmography and an exercise tolerance test were performed prior to and 48 hours following DOX treatment (20 mg/kg, IP) to assess changes in respiratory function and cardiorespiratory capacity. Additional endpoint measures included diaphragm muscle force production and rate of fatigue, plasma testosterone and progesterone levels, and the mitochondrial concentration of DOX and its primary metabolite doxorubicinol (DOXol). Our data show no effect of DOX treatment on respiration (i.e., breathing frequency, tidal volume and minute ventilation) during hypoxic or hypoxic + hypercapnic challenges, with only the hypercapnic challenge resulting in a significant reduction in breathing frequency in both the 2- and 20-month-old rats following acute exposure to DOX. Exercise run time to fatigue was decreased as a function of both age and DOX treatment. Diaphragm specific force production and rate of fatigue development was not different between the two age groups at endpoint. Interestingly, testosterone levels were significantly reduced in the 20-month-old rats compared to 2-months, with no difference in progesterone. Finally, there were no differences in the mitochondrial concentration of DOX or DOXol between age groups. These data demonstrate that acute DOX treatment negatively impacts respiratory muscle function in both 2- and 20-month-old rats. However, further work is needed to understand if age is a key variable in predicting patient vulnerability to DOX respiratory muscle toxicity. Supported by NIH R01 HL144858 and R01 HL146443 to AJS. JJR was supported by the APS Summer Undergraduate Research Fellowship program. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.