bims-hafaim 2025-11-23 papers

Issue of 2025–11–23
two papers selected by
Kyle McCommis, Saint Louis University

bioRxiv. 2025 Sep 30. pii: 2025.09.29.679055. [Epub ahead of print]

PERM1 Gene Delivery via AAV Prevents Heart Failure in a Mouse Model of Pressure Overload.

Karthi Sreedevi, Ryan Montalvo, Abbigail Doku, Audrey Korte, Rebekah Thomas, Sarah Salama, Steven Burrows, Zhen Yan, Alexey V Zaitsev, Junco S Warren.

Heart failure with reduced ejection fraction (HFrEF) remains a leading cause of mortality worldwide. A hallmark of HFrEF is impaired cardiomyocyte contractility accompanied by disrupted mitochondrial bioenergetics; however, no current therapy targets both pathologies simultaneously. PERM1, a striated muscle-specific regulator of mitochondrial bioenergetics, is downregulated in HFrEF patients. We recently demonstrated that overexpression of PERM1 via adeno-associated virus 9 (AAV9-PERM1) enhances both cardiac contractility and mitochondrial biogenesis in C57BL/6 mice. In this study, we evaluated the therapeutic potential of AAV9-PERM1 in a pressure overload-induced mouse model of HFrEF. C57BL/6 mice were treated with either AAV9-PERM1 or control AAV9-GFP (1×10 12 GC/mouse), followed by transverse aortic constriction (TAC) surgery. At 4 weeks post-TAC, control mice receiving AAV-GFP exhibited reduced left ventricular ejection fraction (LVEF), whereas AAV-PERM1 preserved LVEF at baseline levels. This cardioprotective effect was sustained through 8 weeks. Notably, AAV9-PERM1 completely abrogated TAC-induced cardiac hypertrophy and fibrosis. Mitochondrial analysis revealed that AAV9-PERM1 preserved mitochondrial DNA copy number and TFAM protein levels, both of which were reduced by TAC in control hearts. AAV9-PERM1 also improved mitochondrial respiration using pyruvate and octanoylcarnitine as substrates and prevented TAC-induced impairments in oxidative capacity. While PGC-1α expression remained unchanged in control TAC hearts, it was modestly yet significantly upregulated by AAV9-PERM1 in both sham and TAC groups. In addition, AAV9-PERM1 suppressed TAC-induced increases in O-GlcNAcylation, a stress-related posttranslational modification of proteins. Co-immunoprecipitation further revealed interactions of PERM1 with creatine kinase and troponin C, key proteins in ATP transduction and contractility, suggesting a functional coupling between mitochondrial energetics and contractility. In conclusion, AAV-PERM1 gene therapy effectively preserves cardiac function under pressure overload by maintaining mitochondrial biogenesis, respiration capacity and contractility. This study further suggests AAV-PERM1 as a promising therapeutic strategy for HFrEF.

DOI: https://doi.org/10.1101/2025.09.29.679055

bioRxiv. 2025 Sep 29. pii: 2025.09.26.678829. [Epub ahead of print]

Low Dose GLP-1 Therapy Attenuates Pathological Cardiac and Hepatic Remodelling in HFpEF Independent of Weight Loss.

BACKGROUND AND AIMS: Heart failure with preserved ejection fraction (HFpEF) remains a therapeutic challenge. GLP-1 receptor agonists (GLP-1RAs) show clinical promise, and the prevailing hypothesis is that their benefits are primarily driven by weight loss and the downstream benefits of improved functional status. We investigated the weight loss-independent effects of low-dose GLP-1RA therapy in a clinically relevant rodent model of severe cardiometabolic HFpEF.
METHODS: Ten-week-old male ZSF1 obese rats with spontaneous HFpEF were treated with low-dose semaglutide (30 nmol/kg twice weekly, n=6) or vehicle for 16 weeks. Comprehensive assessments included body weight, 2-D echocardiography, invasive hemodynamics, exercise capacity as well as cardiac and hepatic fibrosis and lipid deposition. The study utilized advanced multi-omics approaches, including single-cell RNA sequencing of the heart and liver, as well as cardiac, hepatic and plasma proteomics, to explore underlying mechanisms.
RESULTS: In ZSF1 obese rats, low-dose semaglutide in the absence of weight loss, significantly improved cardiac function, exercise tolerance, and attenuated fibrosis in the heart and liver. Interestingly, semaglutide therapy reduced cardiac and hepatic lipid content as well as lipid droplets in cardiac myocytes and hepatocytes. Mechanistically, multi-omics analyses of cardiac and hepatic tissues revealed that semaglutide exerted these benefits by improving cardiac metabolism, interfering with pro-fibrotic and pro-hypertrophic signals, and by reducing systemic inflammation.
CONCLUSIONS: Low-dose semaglutide provides significant cardioprotective, hepatoprotective, and metabolic benefits in HFpEF independent of weight loss. Our findings support the investigation of lower GLP-1RA dosing in HFpEF and other cardiovascular conditions, including in non-obese patients, to expand the clinical utility of these potent drugs.

Keywords: BCAA; Fibrosis; GLP-1; HFpEF; Semaglutide; ZSF1 Obese Rats

DOI: https://doi.org/10.1101/2025.09.26.678829