Treatment with rapamycin (2 mg/kg every other day) mitigated hypertrophy and delayed the decline in ejection fraction and onset of cardiomyopathy in female, but not male, PHB1 knockdown mice.
Does rapamycin mitigate cardiomyopathy in a cardiomyocyte-specific PHB1 knockdown mouse model?
In a mouse model of PHB1 knockdown-induced dilated cardiomyopathy, mTORC1 inhibition with rapamycin delayed disease progression in females but not males, highlighting a sex-dimorphic role of mTORC1.
Prohibitins 1 and 2 (PHB1/2) are ubiquitously expressed lipid raft proteins that form a multimeric ring supercomplex in cellular membranes where they regulate numerous processes including cellular metabolism, growth, signaling, gene expression and death. PHB1 and -2 are interdependent, such that knockout of one isoform results in knockout of the other, but both isoforms also have distinct functional roles independent of each other that vary by cell type. The role of the PHB supercomplex, and particularly PHB1, in maintaining homeostasis, metabolism and electromechanical function in the heart is not well understood, though emerging evidence suggests that mammalian target of rapamycin complex 1 (mTORC1) may be involved. To address this question, we created a cardiomyocyte-specific PHB1 knockdown (cPHB1ko) mouse model using i.p. tamoxifen injection in homozygous floxxed PHB1 (PHB1fl/fl) MER-Cre-MER positive adult mice (aged ~8 weeks). Six weeks after inducing Cre recombinase expression with tamoxifen, cardiomyocyte PHB1 and PHB2 levels were decreased by >90% in the cPHB1ko mice compared with WT, yet electromechanical function remained unchanged. Cardiac ejection fraction (EF) in the cPHB1ko mice then progressively declined and by 12 weeks post-tamoxifen, mice had developed severe dilated cardiomyopathy and were dead by 14 weeks. Females were more severely impacted by the PHB knockdown, with more rapid onset of cardiomyopathy and mortality compared with males. Integrated transcript-/metabolomic analysis of cPHB1ko hearts at 6 weeks post-tamoxifen showed up-regulation of amino acid metabolism and signaling pathways, coupled with a decline in fatty acid oxidation and glycolysis-related genes. Importantly, these metabolic changes in the cPHB1ko hearts occurred in parallel with substantial up-regulation of mTORC1 activity that was minimally responsive to fasting. This hyper-activated mTORC1 led to impaired autophagy in cPHB1ko hearts, characterized by increased p62, LC3I/II, and Lamp1 levels. Treatment with mTORC1 inhibitor rapamycin at a dose of 2 mg/kg every other day via intraperitoneal injection mitigated hypertrophy and delayed the decline in EF and onset of cardiomyopathy in female, but not male cPHB1ko mice. These findings demonstrate that the PHB complex is a critical regulator of mTORC1 in cardiomyocytes. They further suggest that persistent mTORC1 activity contributes to pathogenesis of cardiomyopathy in female but not male mice, consistent with prior reports of the sexually dimorphic effects of PHB’s in other cardiometabolic disorders. 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.
Torrence et al. (Fri,) conducted a other in Dilated cardiomyopathy. Rapamycin vs. Wild-type mice / untreated cPHB1ko mice was evaluated on Cardiac ejection fraction, development of dilated cardiomyopathy, and mortality. Treatment with rapamycin (2 mg/kg every other day) mitigated hypertrophy and delayed the decline in ejection fraction and onset of cardiomyopathy in female, but not male, PHB1 knockdown mice.