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
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Date
2018-04-27
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Authors
Iñigo, Melissa Mae Raval
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East Carolina University
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.