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Upregulation of IL-8, osteonectin, and myonectin mRNAs by intermittent hypoxia via OCT1- and NRF2-mediated mechanisms in skeletal muscle cells.

ABSTRACT: Sleep apnoea syndrome is characterized by recurrent episodes of oxygen desaturation and reoxygenation (intermittent hypoxia [IH]) and is a risk factor for insulin resistance/Type 2 diabetes. The induction of insulin resistance in skeletal muscle is a key phenomenon to develop diabetes. However, the mechanisms linking IH stress and insulin resistance remain elusive. We exposed human RD and mouse C2C12 muscle cells to normoxia or IH and measured their mRNA levels by real-time RT-PCR. We found that IH significantly increased the mRNA and protein levels of muscle-derived insulin resistance-factors (myokines) such as IL-8, osteonectin (ON), and myonectin (MN) in muscle cells. We further analysed the IH-induced expression mechanisms of IL-8, ON, and MN genes in muscle cells. Deletion analyses of the human myokine promoter(s) revealed that the regions -152 to -151 in IL-8, -105 to -99 in ON, and - 3741 to -3738 in MN promoters were responsible for the activation by IH in RD cells. The promoters contain consensus transcription factor binding sequences for OCT1 in IL-8 and MN promoters, and for NRF2 in ON promoter, respectively. The introduction of siRNA for OCT1 abolished the IH-induced expression(s) of IL-8 and MN and siRNA for NRF2 abolished the IH-induced expression of ON.

SUBMITTER: Takasawa S

PROVIDER: S-EPMC9753449 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Upregulation of IL-8, osteonectin, and myonectin mRNAs by intermittent hypoxia via OCT1- and NRF2-mediated mechanisms in skeletal muscle cells.

Takasawa Shin S Shobatake Ryogo R Itaya-Hironaka Asako A Makino Mai M Uchiyama Tomoko T Sakuramoto-Tsuchida Sumiyo S Takeda Yoshinori Y Ota Hiroyo H Yamauchi Akiyo A

Journal of cellular and molecular medicine 20221201 24

Sleep apnoea syndrome is characterized by recurrent episodes of oxygen desaturation and reoxygenation (intermittent hypoxia [IH]) and is a risk factor for insulin resistance/Type 2 diabetes. The induction of insulin resistance in skeletal muscle is a key phenomenon to develop diabetes. However, the mechanisms linking IH stress and insulin resistance remain elusive. We exposed human RD and mouse C2C12 muscle cells to normoxia or IH and measured their mRNA levels by real-time RT-PCR. We found that ...[more]

PMID: 36457269

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Project description:Nocturnal hypoxaemia, which is common in chronic obstructive pulmonary disease (COPD) patients, is associated with skeletal muscle loss or sarcopenia, which contributes to adverse clinical outcomes. In COPD, we have defined this as prolonged intermittent hypoxia (PIH) because the duration of hypoxia in skeletal muscle occurs through the duration of sleep followed by normoxia during the day, in contrast to recurrent brief hypoxic episodes during obstructive sleep apnoea (OSA). Adaptive cellular responses to PIH are not known. Responses to PIH induced by three cycles of 8 h hypoxia followed by 16 h normoxia were compared to those during chronic hypoxia (CH) or normoxia for 72 h in murine C2C12 and human inducible pluripotent stem cell-derived differentiated myotubes. RNA sequencing followed by downstream analyses were complemented by experimental validation of responses that included both unique and shared perturbations in ribosomal and mitochondrial function during PIH and CH. A sarcopenic phenotype characterized by decreased myotube diameter and protein synthesis, and increased phosphorylation of eIF2α (Ser51) by eIF2α kinase, and of GCN-2 (general controlled non-derepressed-2), occurred during both PIH and CH. Mitochondrial oxidative dysfunction, disrupted supercomplex assembly, lower activity of Complexes I, III, IV and V, and reduced intermediary metabolite concentrations occurred during PIH and CH. Decreased mitochondrial fission occurred during CH. Physiological relevance was established in skeletal muscle of mice with COPD that had increased phosphorylation of eIF2α, lower protein synthesis and mitochondrial oxidative dysfunction. Molecular and metabolic responses with PIH suggest an adaptive exhaustion with failure to restore homeostasis during normoxia. KEY POINTS: Sarcopenia or skeletal muscle loss is one of the most frequent complications that contributes to mortality and morbidity in patients with chronic obstructive pulmonary disease (COPD). Unlike chronic hypoxia, prolonged intermittent hypoxia is a frequent, underappreciated and clinically relevant model of hypoxia in patients with COPD. We developed a novel, in vitro myotube model of prolonged intermittent hypoxia with molecular and metabolic perturbations, mitochondrial oxidative dysfunction, and consequent sarcopenic phenotype. In vivo studies in skeletal muscle from a mouse model of COPD shared responses with our myotube model, establishing the pathophysiological relevance of our studies. These data lay the foundation for translational studies in human COPD to target prolonged, nocturnal hypoxaemia to prevent sarcopenia in these patients.

Project description:BackgroundPosttraumatic osteoarthritis (PTOA) is directly associated with early acute articular cartilage injury. Inhibition of cartilage destruction immediately following joint damage can effectively slow or prevent PTOA progression. Therefore, we sought to determine intervention targets and therapeutic strategies in the acute stage of cartilage injury. The benefits of chronic intermittent hypobaric hypoxia (CIHH) extend to various body tissues, but its impact on acute cartilage injury remains unclear. We selected PTOA initiation as the therapeutic window and administered CIHH treatment immediately following cartilage injury initiation to investigate its protective effect on cartilage and molecular mechanism changing with time-varying.MethodsThe non-invasive PTOA mouse model was established by applying a single rapid specific impact force to the right knee's tibial plateau, initiating load-induced PTOA development, closely resembling the pathological changes in human diseases. Following loading, we inhibited cartilage destruction by treating mice immediately in a hypobaric chamber with a hypobaric hypoxia mimic at 5000 m altitude. Cohorts of mice subjected to distinct experimental conditions were monitored for 3, 7, 14 or 28 days. Safranin O-Fast Green staining, Immunohistochemistry, immunofluorescence, ELISA, and western blotting were performed to evaluate the therapeutic effects of CIHH on cartilage in vivo. The nuclear translocation of NF-κB p65 and Nrf2 were detected by immunofluorescence.ResultsThe results showed that inhibiting cartilage destruction using CIHH immediately following acute articular cartilage injury initiation delayed the progression of PTOA, decreased the Mankin score and suppressed the expression of proinflammatory factors, including iNOS, NO, TNF-α, and IL-1β. Meanwhile, immediate CIHH treatment reduced levels of the catabolic enzymes ADAMTS5 and MMP13 in the cartilage matrix, reversed degradation of Collagen II and COMP, and inhibited oxidative stress by decreasing ROS levels. Moreover, CIHH suppressed NF-κB signaling by activating the Nrf2 in vivo studies.ConclusionOur study demonstrated that immediate CIHH treatment following cartilage injury initiation can attenuate load-induced cartilage damage by activating Nrf2/HO-1 and inhibiting the NF-κB p65 signalling pathways to counteract oxidative stress and inflammatory reactions, enhance the metabolic balance of the cartilage matrix and delay cartilage degeneration. This treatment may represent a potential therapeutic strategy for limiting PTOA progression.

Dataset Information

Upregulation of IL-8, osteonectin, and myonectin mRNAs by intermittent hypoxia via OCT1- and NRF2-mediated mechanisms in skeletal muscle cells.

Publications

Upregulation of IL-8, osteonectin, and myonectin mRNAs by intermittent hypoxia via OCT1- and NRF2-mediated mechanisms in skeletal muscle cells.

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