Sex-Specific Characterization of a Novel Osteoarthritis-Induced Heart Failure Model in Mice

Prasoon, P.; Tammen, K.; Meyyappan, A.; Dalvi, M.; Arnab, S.; Eschborn, M.; Fischer, R.; Kay, M. W.; Mendelowitz, D.; Bethea, J. R.

doi:10.1101/2025.10.16.682846

bioRxiv · 10.1101/2025.10.16.682846

Sex-Specific Characterization of a Novel Osteoarthritis-Induced Heart Failure Model in Mice

Prasoon, P.·Tammen, K.·Meyyappan, A.·Dalvi, M.·Arnab, S.·Eschborn, M.·Fischer, R.·Kay, M. W.·Mendelowitz, D.·Bethea, J. R.

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Abstract

Chronic low-grade inflammation is increasingly recognized as a key driver of heart failure (HF) progression; however, the direct contribution of systemic inflammatory disorders such as osteoarthritis (OA) remains unclear. Here, we establish a murine model of OA-induced HF using destabilization of the medial meniscus (DMM) to induce systemic inflammation and sex-specific cardiac remodeling. Longitudinal echocardiography revealed that females develop diastolic dysfunction with preserved ejection fraction, resembling HFpEF, whereas males exhibit progressive systolic impairment, consistent with a transitional HFmrEF-to-HFrEF phenotype. Morphometric and histological analyses confirmed concentric hypertrophy in females and eccentric remodeling in males. Transcriptomic profiling identified distinct molecular programs--females upregulated extracellular matrix, cytoskeletal, and calcium-handling genes, while males showed enrichment of inflammatory and immune signaling pathways. Immunoblot analyses further validated these sex-specific molecular signatures: females displayed increased ANP, BNP, Sirt1, and AMPK expression, consistent with metabolic resilience and fibrotic remodeling, whereas males exhibited elevated p38 MAPK, NF-{kappa}B, LC3B, and cleaved caspase-3, reflecting heightened inflammation, autophagy, and apoptosis. Both sexes demonstrated downregulation of mitochondrial and lipid metabolic proteins, indicating convergent energetic stress. Collectively, these findings identify OA as a systemic inflammatory driver of heart failure, delineate the molecular and proteomic basis of sex-dependent cardiac remodeling, and introduce a translational preclinical model that recapitulates the clinical heterogeneity of HFpEF and HFmrEF/HFrEF, providing a foundation for mechanistic and therapeutic exploration.

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Prasoon, P., Tammen, K., Meyyappan, A., Dalvi, M., Arnab, S., Eschborn, M., Fischer, R., Kay, M. W., Mendelowitz, D., Bethea, J. R.. 2025-10-16. Sex-Specific Characterization of a Novel Osteoarthritis-Induced Heart Failure Model in Mice. https://doi.org/10.1101/2025.10.16.682846

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