AJSM - 2026-08-12 - Journal Article
Role of Hypoxia-Inducible Factor-1α in Regulating Muscle Degeneration After Rotator Cuff Tears.
Zhang H, Lee A, Liu M, Diaz A, Zhang Y, Kim HT, Feeley BT, Liu X
Topics
Key Takeaway
FAP cell-specific HIF-1α knockout in a murine rotator cuff tear model increased fibrosis by 157% (4.43% vs 1.72%) and reduced myofiber cross-sectional area by 44% (664 vs 1196 µm²), identifying HIF-1α as a pro-adipogenic, anti-fibrotic regulator in rotator cuff muscle degeneration.
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Summary
This controlled laboratory study used a supraspinatus tendon and suprascapular nerve transection (TTDN) murine model to define HIF-1α's role in FAP cell differentiation and secondary muscle degeneration. TTDN reduced capillary density and decreased global HIF-1α expression at 1 and 2 weeks, while FAP cell-specific HIF-1α knockout increased fibrosis (4.43% vs 1.72%), decreased fatty infiltration (0.62% vs 1.55%), and reduced myofiber cross-sectional area (664 vs 1196 µm²). In vitro CRISPR-Cas9 knockdown confirmed HIF-1α suppresses fibrogenesis (via α-SMA) and promotes brown adipose differentiation (via UCP1) specifically in FAP cells, not satellite cells or myocytes.
Key Limitation
The TTDN model combines denervation with tendon transection, and the authors acknowledge that decreased global HIF-1α likely reflects reduced metabolic demand from denervation rather than true tissue hypoxia, limiting direct translational inference to isolated tendon tear pathophysiology in humans.
Original Abstract
BACKGROUND
Secondary muscle degeneration after a rotator cuff tear (RCT) critically affects clinical outcomes. Vascular compromise after a tendon injury creates a complex microenvironment that may be associated with the degeneration of rotator cuff muscle. The role of hypoxia-inducible factor-1α (HIF-1α), a master regulator of cellular stress responses to hypoxia, in modulating muscle abnormalities after an RCT remains undefined.
PURPOSE
To define the role of HIF-1α in stem cell differentiation and muscle degeneration after an RCT in a murine model.
STUDY DESIGN
Controlled laboratory study.
METHODS
A supraspinatus tendon transection and suprascapular nerve transection (TTDN) model was established in C57BL/6J, platelet-derived growth factor receptor α (PDGFRα)-green fluorescent protein (GFP) reporter, and inducible cell-specific HIF-1α knockout mice. Vascularity and HIF-1α colocalization with fibroadipogenic progenitor (FAP) cells and satellite cells were analyzed. Fibrosis, fatty infiltration, and myofiber cross-sectional area were assessed. In vitro, HIF-1α was modulated in isolated FAP cells via CRISPR-Cas9 or prolyl hydroxylase domain inhibitors to evaluate FAP cell differentiation.
RESULTS
TTDN induced significant capillary density reduction (CD31 + ) at 1, 2, and 6 weeks after an injury. Global HIF-1α expression decreased after TTDN compared to the sham side (1 week: 0.78 ± 0.22 vs 1.40 ± 0.42, respectively [ P = .019]; 2 weeks: 0.74 ± 0.51 vs 1.70 ± 0.48, respectively [ P = .015]). The percentage of PDGFRα + FAP cells increased at 6 weeks after TTDN compared to the sham side (15.69% ± 1.90% vs 12.76% ± 0.78%, respectively; P = .013). The percentage of HIF-1α + FAP cells relative to total PDGFRα + cells significantly decreased in the late stage (6 weeks) of an RCT compared to the sham side (2.78% ± 0.90% vs 7.38% ± 2.29%, respectively; P = .003). Knocking out HIF-1α in FAP cells in vivo resulted in increased fibrosis (Cre + : 4.43% ± 2.16% vs Cre - : 1.72% ± 0.39%; P = .047), decreased fatty infiltration (Cre + : 0.62% ± 0.42% vs Cre - : 1.55% ± 0.45%; P = .016), and reduced cross-sectional area (Cre + : 664.71 ± 354.45 vs Cre - : 1195.81 ± 338.66; P = .041). Neither satellite cell-specific nor myocyte-specific HIF-1α deletion resulted in significant phenotypic changes. The downregulation of HIF-1α led to a decrease in uncoupling protein 1 expression and an increase in α-smooth muscle actin expression in FAP cells.
CONCLUSION
Although vascularity was reduced after TTDN, pronounced global tissue hypoxia was not directly evidenced. Decreased global HIF-1α expression may reflect denervation-induced reductions in metabolic demand. HIF-1α emerges as a key player in FAP cell differentiation within the injury microenvironment, promoting brown adipose tissue differentiation and inhibiting fibrogenesis.
CLINICAL RELEVANCE
Targeting HIF-1α in FAP cells offers a novel therapeutic strategy to mitigate secondary muscle atrophy and fibrosis after an RCT.