Targeting mitochondrial dysfunction with the exercise-derived metabolite beta-aminoisobutyric acid protects against doxorubicin-induced cardiomyopathy

Abstract Introduction Exercise is a potent non-pharmacological intervention for cardiovascular health, partly due to circulating factors known as exerkines. Most exerkines are high-molecular-weight proteins or peptides, limiting their pharmacological stability and translational applicability. β-aminoisobutyric acid (BAIBA) is a small, non-proteinogenic amino acid released from skeletal muscle during exercise and is one of the few low-molecular-weight exerkines with favorable safety and bioavailability profiles. Doxorubicin (DOX), a widely used anthracycline anticancer agent, causes serious cardiotoxicity. Although dexrazoxane, an iron chelator, is the only FDA-approved drug for prevention, its use remains restricted due to concerns about cancer recurrence. Therefore, novel preventive strategies are urgently needed. Purpose To investigate whether BAIBA preserves cardiac function in DOX-induced cardiotoxicity and, if any, to explore the underlying mechanisms. Methods Eleven-week-old male C57BL/6J mice received intraperitoneal DOX injections (8.0 mg/kg) once weekly for a total of four doses. Mice were concurrently administered either vehicle or BAIBA (150 mg/kg/day) in drinking water. One week after the final dose, cardiac function was assessed by cardiac MRI, and the hearts were harvested for myocardial proteomics and genomic quantitative PCR. H9c2 cardiomyoblasts were treated with DOX and/or BAIBA to evaluate mitochondrial function via Seahorse XF assays. Results Chronic BAIBA administration elevated plasma BAIBA levels (Fig.A). DOX significantly impaired left ventricular ejection fraction (LVEF) and cardiac index (CI) (vehicle: mean LVEF 56.9 ± 4.4% and CI 0.57 ± 0.1 μL/min/BW vs. DOX: 49.6 ± 4.9% and 0.39 ± 0.1 μL/min/BW, p=0.01). Remarkably, concurrent BAIBA administration restored LVEF (DOX+BAIBA: 58.5 ± 5.4%, p0.01 vs. DOX) and CI (0.47 ± 0.1 μL/min/BW, p=0.03 vs. DOX] (Fig.B). Proteomic analysis revealed that DOX significantly downregulated pathways involved in mitochondrial ATP synthesis normalized enrichment score (NES) -1.97, p0.01, whereas BAIBA co-treatment reversed these alteration (NES +3.04, p0.01) (Fig.C). Genomic qPCR for mitochondrial genome (mtDNA) showed no significant change in mtDNA copy number, suggesting that BAIBA preserved mitochondrial ATP synthesis without altering mitochondrial content (Fig.D). In vitro, Seahorse XF assay in H9c2 cardiomyoblasts demonstrated that DOX significantly reduced oxygen consumption rate (OCR), while BAIBA partially restored mitochondrial respiration, although the change did not reach statistical significance (Fig.E). Conclusions BAIBA preserved cardiac function in DOX-induced cardiotoxicity, accompanied by maintenance of mitochondrial ATP synthesis and respiratory capacity. These findings suggest that BAIBA confers cardioprotection through mitochondria-associated mechanisms and BAIBA may serve as a potential exercise-mimetic strategy to prevent chemotherapy-related cardiomyopathy.For image description, please refer to the figure legend and surrounding text.