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

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.

Inhibitory Acetylation of Pyruvate Dehydrogenase Promotes Diastolic Dysfunction in Mice

ABSTRACTAlterations in cardiac fuel metabolism underpin the development of heart failure with preserved ejection fraction (HFpEF). Mouse models of HFpEF, in addition to changes in fuel choice, display elevated levels of mitochondrial protein acetylation. Reversal of mitochondrial hyperacetylation restores cardiac bioenergetics and function. In this study, we examined the metabolic mechanisms of diastolic dysfunction in diet-induced failing hearts, using a model of constitutively-reduced mitochondrial protein acetylation.

Different fuel regulation in two types of myofiber results in different antioxidant strategies in Daurian ground squirrels (Spermophilus dauricus) during hibernation

We previously showed that different skeletal muscles in Daurian ground squirrels (Spermophilus dauricus) possess different antioxidant strategies during hibernation; however, the reason for these varied strategies remains unclear. To clarify this issue, we studied REDD1, FOXO4, PGC-1α, FOXO1, and atrogin-1 proteins to determine the potential cause of the different antioxidant strategies in Daurian ground squirrels during hibernation, and to clarify whether different strategies affect atrophy-related signals. Results showed that the soleus (SOL) muscle experienced intracellular hypoxia during interbout arousal, but no oxidative stress. This may be due to increased PGC-1α expression enhancing antioxidant capacity in the SOL under hypoxic conditions. Extensor digitorum longus (EDL) muscle showed no change in oxidative stress, hypoxia, or antioxidant capacity during hibernation. The FOXO1 and PGC-1α results strongly suggested differentially regulated fuel metabolism in the SOL and EDL muscles during hibernation, i.e., enhanced lipid oxidation and maintained anaerobic glycolysis, respectively. Atrogin-1 expression did not increase during hibernation in either the SOL or EDL, indicating that protein synthesis was not inhibited by atrogin-1. Thus, our results suggest that different fuel regulation may be one mechanism related to antioxidant defense strategy formation in different kinds of skeletal muscle fibers of Daurian ground squirrels during hibernation.

ADROPIN: A HEPATOKINE MODULATOR OF VASCULAR FUNCTION AND CARDIAC FUEL METABOLISM

Adropin is a nutritionally regulated peptide hormone, secreted primarily by the liver, which modulates metabolic homeostasis in a number of tissues. Growing evidence suggests that adropin is an important regulatory component in a number of cardiovascular pathologies, and may be central to the control of cardiac fuel metabolism and vascular function. In this mini-review, we examine the known facets of adropin biology, discuss open questions in the field, and speculate on the therapeutic potential of targeting adropin-related signaling pathways in cardiovascular diseases.