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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\u20131\u03b1 (HIF-1\u03b1), a master regulator of cellular stress responses to hypoxia, in modulating muscle abnormalities after an RCT remains undefined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Purpose:<\/jats:title>\n                    <jats:p>To define the role of HIF-1\u03b1 in stem cell differentiation and muscle degeneration after an RCT in a murine model.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Study Design:<\/jats:title>\n                    <jats:p>Controlled laboratory study.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>A supraspinatus tendon transection and suprascapular nerve transection (TTDN) model was established in C57BL\/6J, platelet-derived growth factor receptor \u03b1 (PDGFR\u03b1)\u2013green fluorescent protein (GFP) reporter, and inducible cell-specific HIF-1\u03b1 knockout mice. Vascularity and HIF-1\u03b1 colocalization with fibroadipogenic progenitor (FAP) cells and satellite cells were analyzed. Fibrosis, fatty infiltration, and myofiber cross-sectional area were assessed. In vitro, HIF-1\u03b1 was modulated in isolated FAP cells via CRISPR-Cas9 or prolyl hydroxylase domain inhibitors to evaluate FAP cell differentiation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      TTDN induced significant capillary density reduction (CD31\n                      <jats:sup>+<\/jats:sup>\n                      ) at 1, 2, and 6 weeks after an injury. Global HIF-1\u03b1 expression decreased after TTDN compared to the sham side (1 week: 0.78 \u00b1 0.22 vs 1.40 \u00b1 0.42, respectively [\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      = .019]; 2 weeks: 0.74 \u00b1 0.51 vs 1.70 \u00b1 0.48, respectively [\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      = .015]). The percentage of PDGFR\u03b1\n                      <jats:sup>+<\/jats:sup>\n                      FAP cells increased at 6 weeks after TTDN compared to the sham side (15.69% \u00b1 1.90% vs 12.76% \u00b1 0.78%, respectively;\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      = .013). The percentage of HIF-1\u03b1\n                      <jats:sup>+<\/jats:sup>\n                      FAP cells relative to total PDGFR\u03b1\n                      <jats:sup>+<\/jats:sup>\n                      cells significantly decreased in the late stage (6 weeks) of an RCT compared to the sham side (2.78% \u00b1 0.90% vs 7.38% \u00b1 2.29%, respectively;\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      = .003). Knocking out HIF-1\u03b1 in FAP cells in vivo resulted in increased fibrosis (Cre\n                      <jats:sup>+<\/jats:sup>\n                      : 4.43% \u00b1 2.16% vs Cre\n                      <jats:sup>\u2013<\/jats:sup>\n                      : 1.72% \u00b1 0.39%;\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      = .047), decreased fatty infiltration (Cre\n                      <jats:sup>+<\/jats:sup>\n                      : 0.62% \u00b1 0.42% vs Cre\n                      <jats:sup>\u2013<\/jats:sup>\n                      : 1.55% \u00b1 0.45%;\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      = .016), and reduced cross-sectional area (Cre\n                      <jats:sup>+<\/jats:sup>\n                      : 664.71 \u00b1 354.45 vs Cre\n                      <jats:sup>\u2013<\/jats:sup>\n                      : 1195.81 \u00b1 338.66;\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      = .041). Neither satellite cell\u2013specific nor myocyte-specific HIF-1\u03b1 deletion resulted in significant phenotypic changes. The downregulation of HIF-1\u03b1 led to a decrease in uncoupling protein 1 expression and an increase in \u03b1\u2013smooth muscle actin expression in FAP cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion:<\/jats:title>\n                    <jats:p>Although vascularity was reduced after TTDN, pronounced global tissue hypoxia was not directly evidenced. Decreased global HIF-1\u03b1 expression may reflect denervation-induced reductions in metabolic demand. HIF-1\u03b1 emerges as a key player in FAP cell differentiation within the injury microenvironment, promoting brown adipose tissue differentiation and inhibiting fibrogenesis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Clinical Relevance:<\/jats:title>\n                    <jats:p>Targeting HIF-1\u03b1 in FAP cells offers a novel therapeutic strategy to mitigate secondary muscle atrophy and fibrosis after an RCT.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/03635465261469689","type":"journal-article","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T06:57:02Z","timestamp":1786604222000},"page":"2753-2765","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["Role of Hypoxia-Inducible Factor\u20131\u03b1 in Regulating Muscle Degeneration After Rotator Cuff 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