The Regulatory Roles of PPARs in Skeletal Muscle Fuel Metabolism and Inflammation: Impact of PPAR Agonism on Muscle in Chronic Disease, Contraction and Sepsis.

Hannah Crossland,Dumitru Constantin-Teodosiu,Paul L Greenhaff

doi:10.3390/ijms22189775

Abstract

The peroxisome proliferator-activated receptor (PPAR) family of transcription factors has been demonstrated to play critical roles in regulating fuel selection, energy expenditure and inflammation in skeletal muscle and other tissues. Activation of PPARs, through endogenous fatty acids and fatty acid metabolites or synthetic compounds, has been demonstrated to have lipid-lowering and anti-diabetic actions. This review will aim to provide a comprehensive overview of the functions of PPARs in energy homeostasis, with a focus on the impacts of PPAR agonism on muscle metabolism and function. The dysregulation of energy homeostasis in skeletal muscle is a frequent underlying characteristic of inflammation-related conditions such as sepsis. However, the potential benefits of PPAR agonism on skeletal muscle protein and fuel metabolism under these conditions remains under-investigated and is an area of research opportunity. Thus, the effects of PPARγ agonism on muscle inflammation and protein and carbohydrate metabolism will be highlighted, particularly with its potential relevance in sepsis-related metabolic dysfunction. The impact of PPARδ agonism on muscle mitochondrial function, substrate metabolism and contractile function will also be described.

Highlights

Peroxisome proliferator-activated receptors (PPARs) are a group of transcription factors implicated in wide-ranging cellular functions, including lipid metabolism, inflammatory responses and cell proliferation and differentiation [1]
We previously demonstrated in our laboratory that 6 days of administration of the PPARδ agonist, GW610742 [36], resulted in increased activity of β-hydroxy acyl-CoA dehydrogenase (β-HAD) in resting rat soleus muscle, which is a key step in β-oxidation in the mitochondria
We observed that pyruvate dehydrogenase complex (PDC) activity during contraction was significantly less with the PPARδ agonist than control, while anaerobic metabolism was greater. We proposed that this collectively accounted for the observed impaired contractile function with GW610742X agonist, indicating that PPARδ agonism can impair the contrac

Summary

Introduction

Peroxisome proliferator-activated receptors (PPARs) are a group of transcription factors implicated in wide-ranging cellular functions, including lipid metabolism, inflammatory responses and cell proliferation and differentiation [1]. Three PPAR subtypes exist (PPARα, PPARδ and PPARγ) They are activated in vivo by endogenous fatty acids and their metabolites and synthetic compounds developed for their lipid-lowering and anti-diabetic actions. Disturbances in skeletal muscle energy homeostasis play a key part in the pathogenesis of several chronic non-communicable disease conditions, including type 2 diabetes (T2D). This review will aim to provide an overview of the metabolic regulatory roles of PPARs in energy homeostasis, with a focus on the impacts of PPARδ agonism on skeletal muscle metabolism and contractile function, primarily highlighting studies that have involved in vivo/ex vivo animal models or human volunteers. The focus will be directed towards the potential role of PPARγ agonism in alleviating muscle inflammation and metabolic disturbances during sepsis

Metabolic Functions of PPARs and Their Actions in Skeletal Muscle

Activation

PPARγ Agonism and Skeletal Muscle Metabolism and Inflammation

Impact

Conclusions and Future Perspectives