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The Role of Perilipin 5 (PLIN5) in Muscle Metabolism

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thesis
posted on 06.02.2017, 23:35 by Ruzaidi Azli Mohd Mokhtar
The perilipin (PLIN) family of proteins reside on, or near, intracellular lipid droplets and play a major role in the regulation of lipid metabolism in most tissues. PLIN5 is highly expressed in tissues that have a high capacity for fatty acid metabolism, especially skeletal muscle. However, there is very limited knowledge about the function of PLIN5 in skeletal muscle. Therefore, the aims of this thesis were to delineate the role of PLIN5 on substrate metabolism in muscle. Accordingly, we generated whole-body Plin5-/- mice to determine PLIN5’s involvement in lipid metabolism and insulin action in chapter 2. Loss of PLIN5 had no effect on body weight, feeding or adiposity but increased whole-body carbohydrate oxidation. Plin5-/- mice developed skeletal muscle insulin resistance, which was associated with increased intramyocellular triglyceride lipolysis and ceramide accumulation. Liver insulin sensitivity was improved in Plin5-/- mice, indicating tissue-specific effects of PLIN5 on insulin action. Thus, we conclude that PLIN5 plays a critical role in coordinating skeletal muscle triacylglycerol metabolism, which impacts sphingolipid metabolism, and is requisite for the maintenance of skeletal muscle insulin action.
   In chapter 3, we successfully generated mice with muscle-specific ablation of PLIN5 (Plin5MKO) in order to investigate the effects of muscle-specific PLIN5 deletion on energy homeostasis, muscle metabolism and glucose tolerance in vivo. There was an increase in whole-body fatty acid oxidation and reciprocal decrease in carbohydrate oxidation in Plin5MKO mice. Intriguingly, fatty acid and glucose oxidation were not different between genotypes when assessed in skeletal muscle ex vivo. The mismatch between the in vivo and ex vivo studies of fatty acid oxidation indicate that PLIN5 deletion in skeletal muscle may alter endocrine signaling to modulate whole body metabolism. In mice fed a HFD, glucose tolerance was markedly enhanced in Plin5MKO compared with control (lox/lox) mice and this was associated with increased glucose clearance without changes in endogenous glucose production. We proposed that this may be caused by an increase in non-insulin stimulated glucose clearance.
   Lastly, we studied the role of PLIN5 in the regulation of skeletal muscle substrate metabolism during acute exercise. We also assessed whether PLIN5 is required for the metabolic adaptations and enhancement in exercise tolerance following endurance exercise training. Using Plin5MKO mice, we showed that PLIN5 is dispensable for normal substrate metabolism during exercise as reflected by levels of blood metabolites and rates of glycogen and triglyceride depletion that were indistinguishable from lox/lox mice. Plin5MKO mice exhibited a functional impairment in their response to endurance exercise training as reflected by reduced maximal running capacity and reduced time to fatigue during prolonged submaximal exercise. The reduction in exercise performance was not accompanied by alterations in carbohydrate and fatty acid metabolism during submaximal exercise. Similarly, mitochondrial capacity and mitochondrial function was not different between lox/lox and Plin5MKO mice. Thus, PLIN5 is dispensable for normal substrate metabolism during exercise and is not required to promote mitochondrial biogenesis or enhance the cellular adaptations to endurance-exercise training. Together, the work in this thesis extends our understanding of the important role of PLIN5 in skeletal muscle metabolism.

History

Principal supervisor

Matthew James Watt

Additional supervisor 1

Clinton Bruce

Year of Award

2017

Department, School or Centre

Physiology

Campus location

Australia

Course

Doctor of Philosophy

Degree Type

DOCTORATE

Faculty

Faculty of Medicine Nursing and Health Sciences

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