{"doi":"10.1101/2023.06.05.543809","title":"Single Nuclei RNA Sequencing of the Gastrocnemius Muscle in Peripheral Artery Disease","abstract":"ABSTRACT Background Lower extremity peripheral artery disease (PAD) is a growing epidemic with limited effecOve treatment options. Herein, we provide a single nuclei atlas of PAD limb muscle to facilitate a better understanding of the composition of cells and transcriptional differences that comprise the diseased limb muscle. Methods We obtained gastrocnemius muscle specimens from 20 PAD patients and 12 non-PAD controls. Nuclei were isolated and single nuclei RNA sequencing (snRNAseq) was performed. The composition of nuclei was characterized by iteraOve clustering via principal component analysis, differenOal expression analysis, and the use of known marker genes. BioinformaOcs analysis was performed to determine differences in gene expression between PAD and non-PAD nuclei, as well as subsequent analysis of intercellular signaling networks. Additional histological analyses of muscle specimens accompany the snRNAseq atlas. Results snRNAseq analysis indicated a fiber type shim with PAD paOents having fewer Type I (slow/oxidaOve) and more Type II (fast/glycolyOc) myonuclei compared to non-PAD, which was confirmed using immunostaining of muscle specimens. Myonuclei from PAD displayed global upregulation of genes involved in stress response, autophagy, hypoxia, and atrophy. Subclustering of myonuclei also idenOfied populations that were unique to PAD muscle characterized by metabolic dysregulation. PAD muscles also displayed unique transcriptional profiles and increased diversity of transcriptomes in muscle stem cells, regeneraOng myonuclei, and fibro-adipogenic progenitor (FAPs) cells. Analysis of intercellular communication networks revealed FAPs as a major signaling hub in PAD muscle, as well as deficiencies in angiogenic and bone morphogeneOc protein signaling which may contribute to poor limb function in PAD. Conclusions This reference snRNAseq atlas provides a comprehensive analysis of the cell composition, transcriptional signature, and intercellular communication pathways that are altered in the PAD condition.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":396624,"datarank":0.1688640239120984,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"self_citation_contribution":0.16479184330021646,"citation_network_contribution":0.004072180611881943,"self_endowment_contribution":0.16479184330021646,"citer_contribution":0.004072180611881943,"corpus_percentile":32.853717026378895,"corpus_rank":8681,"citation_count":2,"citer_count":1,"citers_with_citation_signal":1,"citers_with_endowment":1,"datacite_reuse_total":0,"is_dataset":true,"is_dataset_confidence":0.8694,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":908460,"name":"Victoria Palzkill","orcid":"0000-0001-9382-169X","position":1,"is_corresponding":false},{"id":1041625,"name":"Jianna Tan","orcid":"0009-0001-6836-6899","position":2,"is_corresponding":false},{"id":354503,"name":"Kyoungrae Kim","orcid":"0000-0001-9513-6469","position":3,"is_corresponding":false},{"id":684771,"name":"Trace Thome","orcid":"0000-0003-4823-8547","position":4,"is_corresponding":false},{"id":629460,"name":"Qingping Yang","orcid":null,"position":5,"is_corresponding":false},{"id":972952,"name":"Brian Fazzone","orcid":"0000-0002-8987-1480","position":6,"is_corresponding":false},{"id":295110,"name":"Scott T. Robinson","orcid":"0000-0002-2911-439X","position":7,"is_corresponding":false},{"id":781100,"name":"Kerri A. O’Malley","orcid":null,"position":8,"is_corresponding":false},{"id":235524,"name":"Feng Yue","orcid":"0000-0002-5856-3506","position":9,"is_corresponding":false},{"id":354505,"name":"Salvatore T. Scali","orcid":"0000-0002-8128-3203","position":10,"is_corresponding":false},{"id":506920,"name":"Scott A. Berceli","orcid":"0000-0003-2257-0111","position":11,"is_corresponding":false},{"id":354506,"name":"Terence E. Ryan","orcid":"0000-0003-0780-029X","position":12,"is_corresponding":false},{"id":1041624,"name":"Caroline Pass","orcid":"0009-0003-4234-8777","position":0,"is_corresponding":true}],"reference_count":120,"raw_metadata":null,"created_at":"2026-07-19T01:19:31.472087Z","pmid":null,"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":[]}