Induced ablation of skeletal muscle-specific estrogen receptor-alpha in adult female mice increased the susceptibility to develop skeletal muscle inflammation and glucose intolerance under chronic lipid overload

ECU Author/Contributor (non-ECU co-authors, if there are any, appear on document)

Melissa Mae Raval Iñigo (Creator)

Institution

East Carolina University (ECU )

Web Site: http://www.ecu.edu/lib/

Abstract: Skeletal muscle-specific ER[alpha] appears to play important roles in regulating skeletal muscle glucose and lipid homeostasis. The overall aim of this dissertation was to determine whether skeletal muscle-specific ER[alpha] is critical for maintaining metabolic function under conditions of lipid overload. To further advance our understanding of skeletal muscle-specific ER[alpha] , this study integrated in vivo and in vitro loss-of-function approaches by generating a novel inducible skeletal muscle-specific ER[alpha] knockout mouse model (ER[alpha]KOism) and by silencing ER[alpha] in human myotubes using an adenovirus-driven ER[alpha]shRNA. The overarching hypothesis is that induced ablation of skeletal muscle-specific ER[alpha] increased the susceptibility to high fat diet (HFD)-induced metabolic dysfunction. ER[alpha]KOism mice exhibited similar adiposity after acute and chronic HFD treatments compared to WT mice , for both females and males. Indirect calorimetry revealed that energy expenditure was similar between female WT and ER[alpha]KOism mice , even when exposed to acute and chronic HFD treatments. Male ER[alpha]KOism mice exhibited minimally greater energy expenditure after chronic HFD treatment compared to male WT mice , regardless of diet. Spontaneous cage activity was similar between diet-matched WT and ER[alpha]KOism mice for both sexes , even after acute and chronic HFD treatment. Analysis of glucose dynamics revealed that female ER[alpha]KOism-HFD exhibited greater glucose intolerance than WT-HFD after chronic HFD treatment. Ex vivo skeletal muscle glucose uptake was similar between female WT and ER[alpha]KOism mice , although GLUT4 protein content was lower in skeletal muscle of female ER[alpha]KOism , regardless of diet. Markers of pro-inflammation were also elevated in female ER[alpha]KOism mice , regardless of diet. Analysis of mitochondrial respiratory capacity , oxidative phosphorylation efficiency , and H2O2 emission potential in permeabilized skeletal muscle fibers , revealed that skeletal muscle mitochondrial function was similar between WT and ER[alpha]KOism for both sexes. In human skeletal myotubes sourced from healthy and obese-insulin resistant adult women , ATP production rate was minimally lower in myotubes transduced with ER[alpha]shRNA compared to scrambled-shRNA (control) myotubes. Overall , the data suggest that skeletal muscle ER[alpha] is critical for maintaining glucose tolerance in females on a chronic HFD and regulating skeletal muscle inflammation.

Additional Information

Publication

Dissertation

Language: English

Date: 2018

Keywords

metabolism, mitochondrial respiration, OXPHOS efficiency, H2O2 emission potential, glucose tolerance

Subjects

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