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The DUX4-HIF1α Axis in Murine and Human Muscle Cells: A Link More Complex Than Expected.

ABSTRACT: FacioScapuloHumeral muscular Dystrophy (FSHD) is one of the most prevalent inherited muscle disorders and is linked to the inappropriate expression of the DUX4 transcription factor in skeletal muscles. The deregulated molecular network causing FSHD muscle dysfunction and pathology is not well understood. It has been shown that the hypoxia response factor HIF1α is critically disturbed in FSHD and has a major role in DUX4-induced cell death. In this study, we further explored the relationship between DUX4 and HIF1α. We found that the DUX4 and HIF1α link differed according to the stage of myogenic differentiation and was conserved between human and mouse muscle. Furthermore, we found that HIF1α knockdown in a mouse model of DUX4 local expression exacerbated DUX4-mediated muscle fibrosis. Our data indicate that the suggested role of HIF1α in DUX4 toxicity is complex and that targeting HIF1α might be challenging in the context of FSHD therapeutic approaches.

SUBMITTER: Nguyen TH

PROVIDER: S-EPMC10969790 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature

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The DUX4-HIF1α Axis in Murine and Human Muscle Cells: A Link More Complex Than Expected.

Nguyen Thuy-Hang TH Limpens Maelle M Bouhmidi Sihame S Paprzycki Lise L Legrand Alexandre A Declèves Anne-Emilie AE Heher Philipp P Belayew Alexandra A Banerji Christopher R S CRS Zammit Peter S PS Tassin Alexandra A

International journal of molecular sciences 20240315 6

FacioScapuloHumeral muscular Dystrophy (FSHD) is one of the most prevalent inherited muscle disorders and is linked to the inappropriate expression of the DUX4 transcription factor in skeletal muscles. The deregulated molecular network causing FSHD muscle dysfunction and pathology is not well understood. It has been shown that the hypoxia response factor HIF1α is critically disturbed in FSHD and has a major role in DUX4-induced cell death. In this study, we further explored the relationship betw ...[more]

PMID: 38542301

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Project description:BackgroundHypoxia is known to modify skeletal muscle biological functions and muscle regeneration. However, the mechanisms underlying the effects of hypoxia on human myoblast differentiation remain unclear. The hypoxic response pathway is of particular interest in patients with hereditary muscular dystrophies since many present respiratory impairment and muscle regeneration defects. For example, an altered hypoxia response characterizes the muscles of patients with facioscapulohumeral dystrophy (FSHD).MethodsWe examined the impact of hypoxia on the differentiation of human immortalized myoblasts (LHCN-M2) cultured in normoxia (PO2: 21%) or hypoxia (PO2: 1%). Cells were grown in proliferation (myoblasts) or differentiation medium for 2 (myocytes) or 4 days (myotubes). We evaluated proliferation rate by EdU incorporation, used myogenin-positive nuclei as a differentiation marker for myocytes, and determined the fusion index and myosin heavy chain-positive area in myotubes. The contribution of HIF1α was studied by gain (CoCl2) and loss (siRNAs) of function experiments. We further examined hypoxia in LHCN-M2-iDUX4 myoblasts with inducible expression of DUX4, the transcription factor underlying FSHD pathology.ResultsWe found that the hypoxic response did not impact myoblast proliferation but activated precocious myogenic differentiation and that HIF1α was critical for this process. Hypoxia also enhanced the late differentiation of human myocytes, but in an HIF1α-independent manner. Interestingly, the impact of hypoxia on muscle cell proliferation was influenced by dexamethasone. In the FSHD pathological context, DUX4 suppressed HIF1α-mediated precocious muscle differentiation.ConclusionHypoxia stimulates myogenic differentiation in healthy myoblasts, with HIF1α-dependent early steps. In FSHD, DUX4-HIF1α interplay indicates a novel mechanism by which DUX4 could interfere with HIF1α function in the myogenic program and therefore with FSHD muscle performance and regeneration.

Project description:BACKGROUND:Performing daily activities independently becomes more difficult in time for patients with Duchenne muscular dystrophy (DMD) due to muscle weakness. When performing seated daily activities, the trunk plays an indispensable role besides the upper extremities. However, knowledge is lacking on the interaction between trunk and upper extremities. Therefore the aim was to investigate whether patients with DMD use trunk movement to compensate for reduced arm function when performing seated tasks, and whether this is related to increased muscle activity. METHODS:Eighteen boys with DMD and twenty-five healthy controls (HC) performed several tasks when sitting unsupported, like reaching (and placing) forward and sideward, drinking and displacing a dinner plate. Maximum joint torque and maximum surface electromyography (sEMG) were measured during maximum voluntary isometric contractions. Three-dimensional movements and normalized sEMG when performing tasks were analyzed. RESULTS:Significantly decreased maximum joint torque was found in DMD patients compared to HC. Trunk and shoulder torques were already decreased in early disease stages. However, only maximum trunk rotation and shoulder abduction torque showed a significant association with Brooke scale. In all reaching and daily tasks, the range of motion in lateral bending and/or flexion-extension was significantly larger in DMD patients compared to HC. The trunk movements did not significantly increase with task difficulty (e.g. increasing object weight) or Brooke scale. Normalized muscle activity was significantly higher in DMD patients for all tasks and muscles. CONCLUSIONS:Boys with DMD use increased trunk movements to compensate for reduced arm function, even when performing relatively simple tasks. This was combined with significantly increased normalized muscle activity. Clinicians should take the trunk into account when assessing function and for intervention development, because DMD patients may appear to have a good trunk function, but percentage of muscle capacity used to perform tasks is increased.

Project description:Background/objectivesObesity (body mass index (BMI)⩾30 kg m-2) is associated with an increased risk of estrogen-dependent breast cancer after menopause. Levels of aromatase, the rate-limiting enzyme in estrogen biosynthesis, are elevated in breast tissue of obese women. Recently, the regulation of aromatase by the p53-hypoxia-inducible factor-1α (HIF1α)/pyruvate kinase M2 (PKM2) axis was characterized in adipose stromal cells (ASCs) of women with Li-Fraumeni Syndrome, a hereditary cancer syndrome that predisposes to estrogen-dependent breast cancer. The current study aimed to determine whether stimulation of aromatase by obesity-associated adipokine leptin involves the regulation of the p53-HIF1α/PKM2 axis.Subjects/methodsHuman breast ASCs were used to characterize the p53-HIF1α/PKM2-aromatase axis in response to leptin. The effect of pharmacological or genetic modulation of protein kinase C (PKC), mitogen-activated protein kinase (MAPK), p53, Aha1, Hsp90, HIF1α and PKM2 on aromatase promoter activity, expression and enzyme activity was examined. Semiquantitative immunofluorescence and confocal imaging were used to assess ASC-specific protein expression in formalin-fixed paraffin-embedded tissue sections of breast of women and mammary tissue of mice following a low-fat (LF) or high-fat (HF) diet for 17 weeks.ResultsLeptin-mediated induction of aromatase was dependent on PKC/MAPK signaling and the suppression of p53. This, in turn, was associated with an increase in Aha1 protein expression, activation of Hsp90 and the stabilization of HIF1α and PKM2, known stimulators of aromatase expression. Consistent with these findings, ASC-specific immunoreactivity for p53 was inversely associated with BMI in breast tissue, while HIF1α, PKM2 and aromatase were positively correlated with BMI. In mice, HF feeding was associated with significantly lower p53 ASC-specific immunoreactivity compared with LF feeding, while immunoreactivity for HIF1α, PKM2 and aromatase were significantly higher.ConclusionsOverall, findings demonstrate a novel mechanism for the obesity-associated increase in aromatase in ASCs of the breast and support the study of lifestyle interventions, including weight management, which may reduce breast cancer risk via effects on this pathway.

Project description:BackgroundMetastasis is the major cause of morbidity and mortality in cancer that involves in multiple steps including epithelial-mesenchymal transition (EMT) process. Centrosome is an organelle that functions as the major microtubule organizing center (MTOC), and centrosome abnormalities are commonly correlated with tumor aggressiveness. However, the conclusive mechanisms indicating specific centrosomal proteins participated in tumor progression and metastasis remain largely unknown.MethodsThe expression levels of centriolar/centrosomal genes in various types of cancers were first examined by in silico analysis of the data derived from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and European Bioinformatics Institute (EBI) datasets. The expression of STIL (SCL/TAL1-interrupting locus) protein in clinical specimens was further assessed by Immunohistochemistry (IHC) analysis and the oncogenic roles of STIL in tumorigenesis were analyzed using in vitro and in vivo assays, including cell migration, invasion, xenograft tumor formation, and metastasis assays. The transcriptome differences between low- and high-STIL expression cells were analyzed by RNA-seq to uncover candidate genes involved in oncogenic pathways. The quantitative polymerase chain reaction (qPCR) and reporter assays were performed to confirm the results. The chromatin immunoprecipitation (ChIP)-qPCR assay was applied to demonstrate the binding of transcriptional factors to the promoter.ResultsThe expression of STIL shows the most significant increase in lung and various other types of cancers, and is highly associated with patients' survival rate. Depletion of STIL inhibits tumor growth and metastasis. Interestingly, excess STIL activates the EMT pathway, and subsequently enhances cancer cell migration and invasion. Importantly, we reveal an unexpected role of STIL in tumor metastasis. A subset of STIL translocate into nucleus and associate with FOXM1 (Forkhead box protein M1) to promote tumor metastasis and stemness via FOXM1-mediated downstream target genes. Furthermore, we demonstrate that hypoxia-inducible factor 1α (HIF1α) directly binds to the STIL promoter and upregulates STIL expression under hypoxic condition.ConclusionsOur findings indicate that STIL promotes tumor metastasis through the HIF1α-STIL-FOXM1 axis, and highlight the importance of STIL as a promising therapeutic target for lung cancer treatment.

Dataset Information

The DUX4-HIF1α Axis in Murine and Human Muscle Cells: A Link More Complex Than Expected.

Publications

The DUX4-HIF1α Axis in Murine and Human Muscle Cells: A Link More Complex Than Expected.

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