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Response: Commentary on the effects of hypoxia on energy substrate use during exercise.

ABSTRACT: BACKGROUND:A recent commentary has been published on our meta-analysis, which investigated substrate oxidation during exercise matched for relative intensities in hypoxia compared with normoxia. Within this commentary, the authors proposed that exercise matched for absolute intensities in hypoxia compared with normoxia, should have been included within the analysis, as this model provides a more suitable experimental design when considering nutritional interventions in hypoxia. MAIN BODY:Within this response, we provide a rationale for the use of exercise matched for relative intensities in hypoxia compared with normoxia. Specifically, we argue that this model provides a physiological stimulus replicable of real world situations, by reducing the absolute workload undertaken in hypoxia. Further, the use of exercise matched for relative intensities isolates the metabolic response to hypoxia, rather than the increased relative exercise intensity experienced in hypoxia when utilising exercise matched for absolute intensities. In addition, we also report previously unpublished data analysed at the time of the original meta-analysis, assessing substrate oxidation during exercise matched for absolute intensities in hypoxia compared with normoxia. CONCLUSION:An increased reliance on carbohydrate oxidation was observed during exercise matched for absolute intensities in hypoxia compared with normoxia. These data now provide a comparable dataset for the use of researchers and practitioners alike in the design of nutritional interventions for relevant populations.

SUBMITTER: Griffiths A

PROVIDER: S-EPMC6924012 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Response: Commentary on the effects of hypoxia on energy substrate use during exercise.

Griffiths Alex A Shannon Oliver O Matu Jamie J King Roderick R Deighton Kevin K O'Hara John P JP

Journal of the International Society of Sports Nutrition 20191219 1

<h4>Background</h4>A recent commentary has been published on our meta-analysis, which investigated substrate oxidation during exercise matched for relative intensities in hypoxia compared with normoxia. Within this commentary, the authors proposed that exercise matched for absolute intensities in hypoxia compared with normoxia, should have been included within the analysis, as this model provides a more suitable experimental design when considering nutritional interventions in hypoxia.<h4>Main b ...[more]

PMID: 31856846

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Project description:Tissue engineering strategies often aim to direct tissue formation by mimicking conditions progenitor cells experience within native tissues. For example, to create cartilage in vitro, researchers often aim to replicate the biochemical and mechanical milieu cells experience during cartilage formation in the developing limb bud. This includes stimulating progenitors with TGF-?1/3, culturing under hypoxic conditions, and regulating mechanosensory pathways using biomaterials that control substrate stiffness and/or cell shape. However, as progenitors differentiate down the chondrogenic lineage, the pathways that regulate their responses to mechanotransduction, hypoxia and TGF-? may not act independently, but rather also impact one another, influencing overall cell response. Here, to better understand hypoxia's influence on mechanoregulatory-mediated chondrogenesis, we cultured human marrow stromal/mesenchymal stem cells (hMSC) on soft (0.167?kPa) or stiff (49.6?kPa) polyacrylamide hydrogels in chondrogenic medium containing TGF-?3. We then compared cell morphology, phosphorylated myosin light chain 2 staining, and chondrogenic gene expression under normoxic and hypoxic conditions, in the presence and absence of pharmacological inhibition of cytoskeletal tension. We show that on soft compared to stiff substrates, hypoxia prompts hMSC to adopt more spread morphologies, assemble in compact mesenchymal condensation-like colonies, and upregulate NCAM expression, and that inhibition of cytoskeletal tension negates hypoxia-mediated upregulation of molecular markers of chondrogenesis, including COL2A1 and SOX9. Taken together, our findings support a role for hypoxia in regulating hMSC morphology, cytoskeletal tension and chondrogenesis, and that hypoxia's effects are modulated, at least in part, by mechanosensitive pathways. Our insights into how hypoxia impacts mechanoregulation of chondrogenesis in hMSC may improve strategies to develop tissue engineered cartilage. STATEMENT OF SIGNIFICANCE: Cartilage tissue engineering strategies often aim to drive progenitor cell differentiation by replicating the local environment of the native tissue, including by regulating oxygen concentration and mechanical stiffness. However, the pathways that regulate cellular responses to mechanotransduction and hypoxia may not act independently, but rather also impact one another. Here, we show that on soft, but not stiff surfaces, hypoxia impacts human MSC (hMSC) morphology and colony formation, and inhibition of cytoskeletal tension negates the hypoxia-mediated upregulation of molecular markers of chondrogenesis. These observations suggest that hypoxia's effects during hMSC chondrogenesis are modulated, at least in part, by mechanosensitive pathways, and may impact strategies to develop scaffolds for cartilage tissue engineering, as hypoxia's chondrogenic effects may be enhanced on soft materials.

Project description:IntroductionUromodulin (UMOD) is a glycoprotein expressed by the epithelial cells of the thick ascending limb of Henle's loop in the kidney. Research has shown that increased uromodulin expression may be associated with lower risk of cardiovascular disease in adults. Utilizing the Blood and Clot Thrombectomy Registry and Collaboration (BACTRAC) (clinicaltrials.gov NCT03153683), a continuously enrolling tissue bank, we aimed to examine the associations between serum uromodulin, age, and high BMI (BMI>25) and its relationship to stroke in patients.MethodsArterial blood distal and proximal to the thrombus was collected during a thrombectomy procedure using the BACTRAC protocol and sent to Olink (Boston, MA) to determine proteomic expression via proximity extension assay. Uromodulin expression was recorded and analyzed using two tailed T-tests and linear regressions.ResultsThe relationship between systemic and intracranial uromodulin, age, high BMI and hypertension were assessed. Systemic and intracranial uromodulin decreased with age (p<0.0001 and r2=0.343, p=0.0416 and r2=0.102) respectively. Systemic uromodulin expression increased with BMI>25 (p=0.014). Presence of hypertension decreased uromodulin's expression systemically (p=0.018) and intracranially (p=0.007).ConclusionsUromodulin was increased significantly in overweight patients, decreased significantly in older patients, and decreased in patients with hypertension. The increase in uromodulin in people with high BMI could be a protective reaction of the kidney to worsening conditions that make ischemic stroke more likely, with a goal of delaying dangerous outcomes. The decreased expression of uromodulin in older adults could be associated with the decline of general kidney function that accompanies aging. Hypertension can contribute to an AKI by decreasing perfusion to the kidney, therefore decreasing kidney function and uromodulin production. Further analyses are needed to understand the role of uromodulin following ischemic stroke.

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Response: Commentary on the effects of hypoxia on energy substrate use during exercise.

Publications

Response: Commentary on the effects of hypoxia on energy substrate use during exercise.

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