{"doi":"10.1101/2025.09.29.679055","title":"PERM1 Gene Delivery via AAV Prevents Heart Failure in a Mouse Model of Pressure Overload","abstract":"Abstract 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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":576611,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9485,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":728549,"name":"Ryan N. Montalvo","orcid":"0000-0002-0323-4545","position":1,"is_corresponding":false},{"id":1485457,"name":"Abigail Oforiwaa Doku","orcid":"0000-0001-7585-7330","position":2,"is_corresponding":false},{"id":1485849,"name":"Audrey Korte","orcid":null,"position":3,"is_corresponding":false},{"id":1269001,"name":"Rebekah Thomas","orcid":null,"position":4,"is_corresponding":false},{"id":1485850,"name":"Sarah Salama","orcid":null,"position":5,"is_corresponding":false},{"id":1485458,"name":"Stephen D. Burrows","orcid":"0000-0002-0227-5222","position":6,"is_corresponding":false},{"id":260532,"name":"Zhen Yan","orcid":"0000-0002-4826-9813","position":7,"is_corresponding":false},{"id":1268555,"name":"Alexey V. Zaitsev","orcid":"0000-0002-8139-1378","position":8,"is_corresponding":false},{"id":480986,"name":"Junco S. Warren","orcid":"0000-0001-5231-4181","position":9,"is_corresponding":false},{"id":1268554,"name":"Karthi Sreedevi","orcid":"0000-0002-8239-3025","position":0,"is_corresponding":true}],"reference_count":55,"raw_metadata":null,"created_at":"2026-07-19T02:58:00.620755Z","pmid":"41256646","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}