Natural products, PGC-1 α , and Duchenne muscular dystrophy

Abstract

Peroxisome proliferator-activated receptor γ (PPARγ) is a transcriptional coactivator that binds to a diverse range of transcription factors. PPARγ coactivator 1 (PGC-1) coactivators possess an extensive range of biological effects in different tissues, and play a key part in the regulation of the oxidative metabolism, consequently modulating the production of reactive oxygen species, autophagy, and mitochondrial biogenesis. Owing to these findings, a large body of studies, aiming to establish the role of PGC-1 in the neuromuscular system, has shown that PGC-1 could be a promising target for therapies targeting neuromuscular diseases. Among these, some evidence has shown that various signaling pathways linked to PGC-1α are deregulated in muscular dystrophy, leading to a reduced capacity for mitochondrial oxidative phosphorylation and increased reactive oxygen species (ROS) production. In the light of these results, any intervention aimed at activating PGC-1 could contribute towards ameliorating the progression of muscular dystrophies. PGC-1α is influenced by different patho-physiological/pharmacological stimuli. Natural products have been reported to display modulatory effects on PPARγ activation with fewer side effects in comparison to synthetic drugs. Taken together, this review summarizes the current knowledge on Duchenne muscular dystrophy, focusing on the potential effects of natural compounds, acting as regulators of PGC-1α.

Keywords: AAV, adeno-associated virus; AMP, adenosine monophosphate; AMPK, 5′ adenosine monophosphate-activated protein kinase; ASO, antisense oligonucleotides; ATF2, activating transcription factor 2; ATP, adenosine triphosphate; BMD, Becker muscular dystrophy; COPD, chronic obstructive pulmonary disease; CREB, cyclic AMP response element-binding protein; CnA, calcineurin a; DAGC, dystrophin-associated glycoprotein complex; DGC, dystrophin–glycoprotein complex; DMD, Duchenne muscular dystrophy; DRP1, dynamin-related protein 1; DS, Down syndrome; ECM, extracellular matrix; EGCG, epigallocatechin-3-gallate; ERRα, estrogen-related receptor alpha; FDA, U. S. Food and Drug Administration; FGF, fibroblast growth factor; FOXO1, forkhead box class-O1; GABP, GA-binding protein; GPX, glutathione peroxidase; GSK3b, glycogen synthase kinase 3b; HCT, hydrochlorothiazide; HDAC, histone deacetylase; HIF-1α, hypoxia-inducible factors; IL, interleukin; LDH, lactate dehydrogenase; MCP-1, monocyte chemoattractant protein-1; MD, muscular dystrophy; MEF2, myocyte enhancer factor 2; MSCs, mesenchymal stem cells; Mitochondrial oxidative phosphorylation; Muscular dystrophy; MyoD, myogenic differentiation; NADPH, nicotinamide adenine dinucleotide phosphate; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NMJ, neuromuscular junctions; NO, nitric oxide; NOS, NO synthase; Natural product; PDGF, platelet derived growth factor; PGC-1, peroxisome proliferator-activated receptor γ coactivator 1; PPARγ activation; PPARγ, peroxisome proliferator-activated receptor γ; Peroxisome proliferator-activated receptor γ coactivator 1α; ROS, reactive oxygen species; Reactive oxygen species; SIRT1, silent mating type information regulation 2 homolog 1; SOD, superoxide dismutase; SPP1, secreted phosphoprotein 1; TNF-α, tumor necrosis factor-α; UCP, uncoupling protein; VEGF, vascular endothelial growth factor; cGMP, cyclic guanosine monophosphate; iPSCs, induced pluripotent stem cells; p38 MAPK, p38 mitogen-activated protein kinase.