HDAC4 Genomic Methylation and Subsequent DNA Binding Following Joint Injury Confers a Sustained Epigenetic Memory of Disrupted Muscle Plasticity

• DOI: 10.1152/physiol.2024.39.s1.1574
• Publication Date: 2024-05-21T14:57:50Z
• Authors: Nicholas Thomas; Alexander Keeble; Allison Owen; Camille Brightwell; Brian Noehren; Yuan Wen; Christopher Fry
• Keywords: 0301 basic medicine; 03 medical and health sciences

Joint injury is associated with protracted atrophy and weakness that poorly recovers; our objective was to define molecular effectors of lost muscle size, strength, plasticity following joint injury. We hypothesized epigenetic imprinting in impairs contributes poor functional recovery surgical repair. recruited a total sixteen ACL-injured participants from whom we obtained vastus lateralis biopsies Pre-, 7-days post-, 4-months post- reconstruction surgery (Sx) strength measures up 6-months post-Sx. performed immunohistochemistry, RNA-seq, reduced representation bisulfite sequencing (RRBS), HDAC4 chromatin immunoprecipitation (HDAC4 ChIP-seq) determine the impact epigenetics gene expression on histological profiles, size Binding Expression Target Analysis (BETA) DNA methylation revealed conserved 985bp regulatory genomic region differentially methylated upstream promoter. observed 108 (Pre-Sx), 111 (7d post-Sx), 110 (4-months post-Sx) promoter sites which 95 were common across all timepoints injured limb. Additionally, 1293 intragenic within locus also Altered 2.2 4.3 fold change transcript abundance Pre-Sx 7d post-Sx, respectively (FDR < 0.05). Notably, binding critical contractile genes coincided their downregulation post-Sx (Log 2 change: ACTA1: -2.02; CKM: -0.97; ATP2A1: -2.34; HOMER2: -1.09; FDR<0.05). these lower mean fiber cross-sectional area limb compared Healthy (Healthy: 4845 ± 213.4μm ; pre-Sx: 4313 190.6μm , p<0.05; post-Sx: 3685 228.1μm 3422 142.8μm p<0.05) peak torque 174.8 10.72nm; 135.2 10.19nm, 82.64 6.80nm, 105.9 8.26nm, sustained throughout follow-up. Our results suggest confers promoter-proximal by increases HDAC4-DNA represses regulating function. This program likely prolonged deficits work supported NIH-NIAMS R01 AR072061. full abstract presented at American Physiology Summit 2024 meeting only available HTML format. There are no additional versions or content for this abstract. not involved peer review process.