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Myeloid hypoxia-inducible factor-1? is essential for skeletal muscle regeneration in mice.

ABSTRACT: The outstanding regeneration ability of skeletal muscle is based on stem cells that become activated and develop to myoblasts after myotrauma. Proliferation and growth of myoblasts result in self-renewal of skeletal muscle. In this article, we show that myotrauma causes a hypoxic microenvironment leading to accumulation of the transcription factor hypoxia-inducible factor-1 (HIF-1) in skeletal muscle cells, as well as invading myeloid cells. To evaluate the impact of HIF-1 in skeletal muscle injury and repair, we examined mice with a conditional HIF-1? knockout targeted to skeletal muscle or myeloid cells in a model of soft tissue trauma. No differences in acute trauma size were detected between control and HIF-1? knockout mice. However, muscles of myeloid HIF-1? knockout mice showed a significant delay in myoblast proliferation and growth of regenerating myofibers, in association with decreased expression of cyclooxygenase-2 in HIF-1?-deficient myeloid cells. Moreover, the removal of necrotic cell debris and the regeneration of endothelial cell structure were impaired in myeloid HIF-1? knockout mice that showed delayed invasion of macrophages to the injury site. Our findings for the first time, to our knowledge, demonstrate that myeloid HIF-1? is required for adequate skeletal muscle regeneration.

SUBMITTER: Scheerer N

PROVIDER: S-EPMC6614040 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Myeloid hypoxia-inducible factor-1α is essential for skeletal muscle regeneration in mice.

Scheerer Nina N Dehne Nathalie N Stockmann Christian C Swoboda Sandra S Baba Hideo A HA Neugebauer Agnes A Johnson Randall S RS Fandrey Joachim J

Journal of immunology (Baltimore, Md. : 1950) 20130531 1

The outstanding regeneration ability of skeletal muscle is based on stem cells that become activated and develop to myoblasts after myotrauma. Proliferation and growth of myoblasts result in self-renewal of skeletal muscle. In this article, we show that myotrauma causes a hypoxic microenvironment leading to accumulation of the transcription factor hypoxia-inducible factor-1 (HIF-1) in skeletal muscle cells, as well as invading myeloid cells. To evaluate the impact of HIF-1 in skeletal muscle inj ...[more]

PMID: 23729446

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Project description:Background and aimsHypoxia inducible factor 1α (HIF1α) plays a critical role in atherosclerosis as demonstrated in endothelial-targeted HIF1α -deficient mice. However, it has not been shown if specific pharmacological inhibitors of HIF1α can be used as potential drugs for atherosclerosis. PX-478 is a selective inhibitor of HIF1α, which was used to reduce cancer and obesity in animal models. Here, we tested whether PX-478 can be used to inhibit atherosclerosis.MethodsWe first tested PX-478 in human aortic endothelial cells (HAEC) and found that it significantly inhibited expression of HIF1α and its targets, including Collagen I. Next, two independent atherosclerosis models, C57BL/6 mice treated with AAV-PCSK9 and ApoE-/- mice, were used to test the efficacy of PX-478. Both mouse models were fed a Western diet for 3 months with bi-weekly treatment with PX-478 (40 mg/kg) or saline.ResultsPX-478 treatment reduced atherosclerotic plaque burden in the aortic trees in both mouse models, while plaque burden in the aortic sinus was reduced in the AAV-PCSK9 mouse model, but not in the ApoE-/- mice. Russell-Movat's Pentachrome and Picrosirius Red staining showed a significant reduction in extracellular matrix remodeling and collagen maturation, respectively, in the PX-478-treated mice. As expected, PX-478 treatment reduced diet-induced weight-gain and abdominal adipocyte hypertrophy. Interestingly, PX-478 reduced plasma LDL cholesterol by 69% and 30% in AAV-PCSK9 and ApoE-/- mice, respectively. To explore the cholesterol-lowering mechanisms, we carried out an RNA sequencing study using the liver tissues from the ApoE-/- mouse study. We found 450 genes upregulated and 381 genes downregulated by PX-478 treatment in the liver. Further, gene ontology analysis showed that PX-478 treatment upregulated fatty acid and lipid catabolic pathways, while downregulating lipid biosynthesis and plasma lipoprotein particle remodeling processes. Of interest, Cfd, Elovl3, and Insig2 were some of the most downregulated genes by PX-478, and have been implicated in fat storage, fatty acid elongation, and cholesterol metabolism. The downregulation of Cfd, Elovl3, and Insig2 was further validated by qPCR in the liver tissues of ApoE-/- mice treated with PX-478.ConclusionsThese results suggest that PX-478 is a potential anti-atherogenic drug, which targets vascular endothelium and hepatic cholesterol pathways.

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Myeloid hypoxia-inducible factor-1? is essential for skeletal muscle regeneration in mice.

Publications

Myeloid hypoxia-inducible factor-1α is essential for skeletal muscle regeneration in mice.

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