{"doi":"10.1172/jci161638","title":"A mitofusin 2/HIF1α axis sets a maturation checkpoint in regenerating skeletal muscle","abstract":"A fundamental issue in regenerative medicine is whether there exist endogenous regulatory mechanisms that limit the speed and efficiency of the repair process. We report the existence of a maturation checkpoint during muscle regeneration that pauses myofibers at a neonatal stage. This checkpoint is regulated by the mitochondrial protein mitofusin 2 (Mfn2), the expression of which is activated in response to muscle injury. Mfn2 is required for growth and maturation of regenerating myofibers; in the absence of Mfn2, new myofibers arrested at a neonatal stage, characterized by centrally nucleated myofibers and loss of H3K27me3 repressive marks at the neonatal myosin heavy chain gene. A similar arrest at the neonatal stage was observed in infantile cases of human centronuclear myopathy. Mechanistically, Mfn2 upregulation suppressed expression of hypoxia-induced factor 1α (HIF1α), which is induced in the setting of muscle damage. Sustained HIF1α signaling blocked maturation of new myofibers at the neonatal-to-adult fate transition, revealing the existence of a checkpoint that delays muscle regeneration. Correspondingly, inhibition of HIF1α allowed myofibers to bypass the checkpoint, thereby accelerating the repair process. We conclude that skeletal muscle contains a regenerative checkpoint that regulates the speed of myofiber maturation in response to Mfn2 and HIF1α activity.","journal":"Journal of Clinical Investigation","year":2022,"id":256841,"datarank":0.4493598410330987,"base_score":2.995732273553991,"endowment":2.995732273553991,"self_citation_contribution":0.4493598410330987,"citation_network_contribution":0.0,"self_endowment_contribution":0.4493598410330987,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":19,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9551,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":323318,"name":"Yuemeng Jia","orcid":"0000-0002-8019-1534","position":1,"is_corresponding":false},{"id":363391,"name":"Jiawei Zhao","orcid":"0000-0003-0682-4601","position":2,"is_corresponding":false},{"id":510117,"name":"Nicholas P. Lesner","orcid":"0000-0001-9734-8828","position":3,"is_corresponding":false},{"id":817202,"name":"Cameron J. Menezes","orcid":"0000-0001-5759-8099","position":4,"is_corresponding":false},{"id":817203,"name":"Spencer D. Shelton","orcid":"0000-0003-1236-5317","position":5,"is_corresponding":false},{"id":890515,"name":"Siva Sai Krishna Venigalla","orcid":"0000-0001-6795-2530","position":6,"is_corresponding":false},{"id":56479,"name":"Jian Xu","orcid":"0000-0003-1988-7337","position":7,"is_corresponding":false},{"id":426420,"name":"Chunyu Cai","orcid":"0000-0001-8808-4779","position":8,"is_corresponding":false},{"id":510119,"name":"Prashant Mishra","orcid":"0000-0003-2223-1742","position":9,"is_corresponding":false},{"id":272401,"name":"Xun Wang","orcid":"0000-0001-5172-0305","position":0,"is_corresponding":true}],"reference_count":79,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T00:25:25.728895Z","pmid":"36125902","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":[]}