HDAC4 is a Mechanistic Driver of Quadriceps Atrophy and Weakness After ACL Injury

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Introduction: Persistent quadriceps weakness and atrophy are among the most significant rehabilitative barriers in patients who have sustained an anterior cruciate ligament (ACL) injury. Despite successful reconstruction surgery (ACLR) and extensive physical rehabilitation, patients can fail to return to pre-injury activity levels. Recent evidence suggests aberrant molecular responses in skeletal muscle underly quadriceps obstinance to recovery after joint injury, however, specific effectors contributing to ACLR quadriceps pathology have yet to be identified. To address this critical gap in knowledge, we employed a large-scale integrative multiomic approach with patient quadriceps biopsies that implicate HDAC4 as a dual contributor to motor endplate degeneration and muscle atrophy following ACLR (Hypothesis). We further evaluated the therapeutic potential of the FDA-approved HDAC inhibitor givinostat in an ACL-transected (ACLT) mouse model. Methods: Human vastus lateralis biopsies were obtained from the injured and contralateral limbs of 26 participants. Repeated injured-limb biopsies were obtained 7 days, 1 month, and 4 months following ACLR. Bulk tissue RNA-seq analysis was performed on all participants and single-nucleus RNAseq (snRNAseq) was performed on a subset of participants (n=5/time point). HDAC4 and H3K27 CHiP-seq was performed on pooled healthy and 7 days post ACLR biopsies. Biopsy sections were processed for immunohistochemistry to analyze fiber size and motor end plate innervation. Quadriceps torque and rate of torque development were assessed via isokinetic dynamometry. A parallel ACLT mouse model tested the effects of givinostat on muscle size, strength, NMJ integrity, and gene expression. Results: We observe significant muscle atrophy 7 days (P< .01) and 4 months (P< .01) following ACLR that is coupled with weakness (4 months, P< .01, 6 months, P< .01) compared to the contralateral limb. We also observe significant motor end plate fragmentation (7 days P< .05, 4 months P< .01) and delocalization of CHRNA1 expression assessed by RNA-FISH. Single nucleus RNA-seq and bulk RNA-seq display significant upregulation (FDR P< .05) of the denervation-responsive HDAC4-MYOG-CHRNA1 signaling cascade from 7 days through 4 months after ACLR, positioning this pathway as a key contributor to motor end plate degeneration. Dual HDAC4 and H3K27 CHIP-sequencing identify HDAC4 binding, histone deacetylation and transcriptional repression of MEF2 family members 7 days after ACLR. In the mouse ACLT model, vehicle treated mice displayed marked atrophy (P< .05), weakness (P< .05), motor end plate fragmentation (P< .05) and induction of denervation responsive genes (FDR P< .05) including Myog, Hdac4, and Chrna1 following ACLT. Givinostat treatment abrogated all pathological outcomes. Conclusion: Our results identify HDAC4 as a mechanistic driver of rapid motor end plate deterioration and quadriceps atrophy in patients who undergo ACLR. We also identify givinostat as a viable therapeutic that may reduce quadriceps dysfunction and reduce barriers to rehabilitation in this patient population. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

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