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Skeletal muscle extracellular matrix remodeling with worsening glycemic control in nonhuman primates.
Ruggiero, Alistaire D; Davis, Ashley; Sherrill, Chrissy; Westwood, Brian; Hawkins, Gregory A; Palmer, Nicholette D; Chou, Jeff W; Reeves, Tony; Cox, Laura A; Kavanagh, Kylie.
Afiliação
  • Ruggiero AD; Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, North Carolina.
  • Davis A; Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, North Carolina.
  • Sherrill C; Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, North Carolina.
  • Westwood B; Department of Hypertension, Wake Forest University School of Medicine, Winston-Salem, North Carolina.
  • Hawkins GA; Center for Precision Medicine, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina.
  • Palmer ND; Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, North Carolina.
  • Chou JW; Center for Precision Medicine, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina.
  • Reeves T; Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, North Carolina.
  • Cox LA; Department of Biostatistics and Data Science, Wake Forest University School of Medicine, Winston-Salem, North Carolina.
  • Kavanagh K; Center for Precision Medicine, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina.
Am J Physiol Regul Integr Comp Physiol ; 320(3): R226-R235, 2021 03 01.
Article em En | MEDLINE | ID: mdl-33206559
Type 2 diabetes (T2D) development may be mediated by skeletal muscle (SkM) function, which is responsible for >80% of circulating glucose uptake. The goals of this study were to assess changes in global- and location-level gene expression, remodeling proteins, fibrosis, and vascularity of SkM with worsening glycemic control, through RNA sequencing, immunoblotting, and immunostaining. We evaluated SkM samples from health-diverse African green monkeys (Cholorcebus aethiops sabaeus) to investigate these relationships. We assessed SkM remodeling at the molecular level by evaluating unbiased transcriptomics in age-, sex-, weight-, and waist circumference-matched metabolically healthy, prediabetic (PreT2D) and T2D monkeys (n = 13). Our analysis applied novel location-specific gene differences and shows that extracellular facing and cell membrane-associated genes and proteins are highly upregulated in metabolic disease. We verified transcript patterns using immunohistochemical staining and protein analyses of matrix metalloproteinase 16 (MMP16), tissue inhibitor of metalloproteinase 2 (TIMP2), and VEGF. Extracellular matrix (ECM) functions to support intercellular communications, including the coupling of capillaries to muscle cells, which was worsened with increasing blood glucose. Multiple regression modeling from age- and health-diverse monkeys (n = 33) revealed that capillary density was negatively predicted by only fasting blood glucose. The loss of vascularity in SkM co-occurred with reduced expression of hypoxia-sensing genes, which is indicative of a disconnect between altered ECM and reduced endothelial cells, and known perfusion deficiencies present in PreT2D and T2D. This report supports that rising blood glucose values incite ECM remodeling and reduce SkM capillarization, and that targeting ECM would be a rational approach to improve health with metabolic disease.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Estado Pré-Diabético / Glicemia / Proteínas da Matriz Extracelular / Diabetes Mellitus Tipo 2 / Músculo Quadríceps / Matriz Extracelular Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Ano de publicação: 2021 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Estado Pré-Diabético / Glicemia / Proteínas da Matriz Extracelular / Diabetes Mellitus Tipo 2 / Músculo Quadríceps / Matriz Extracelular Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Ano de publicação: 2021 Tipo de documento: Article