Redox Homeostasis in Muscular Dystrophies

Abstract

In recent years, growing evidence has suggested a prominent role of oxidative stress in the pathophysiology of several early- and adult-onset muscle disorders, although effective antioxidant treatments are still lacking. Oxidative stress causes cell damage by affecting protein function, membrane structure, lipid metabolism, and DNA integrity, thus interfering with skeletal muscle homeostasis and functionality. Some features related to oxidative stress, such as chronic inflammation, defective regeneration, and mitochondrial damage are shared among most muscular dystrophies, and Nrf2 has been shown to be a central player in antagonizing redox imbalance in several of these disorders. However, the exact mechanisms leading to overproduction of reactive oxygen species and deregulation in the cellular antioxidants system seem to be, to a large extent, disease-specific, and the clarification of these mechanisms in vivo in humans is the cornerstone for the development of targeted antioxidant therapies, which will require testing in appropriately designed clinical trials.

Keywords: FSHD; Nrf2; antioxidants; inflammation; muscular dystrophies; oxidative stress; reactive oxygen species (ROS).

Figure 1

Central role of Nrf2 in protecting muscle from oxidative stress and inflammation. Abbreviations: XO: xanthine oxidase; NOS: nitric oxide synthase; NOX: nicotinamide adenine dinucleotide phosphate oxidases, ROS: reactive oxygen species; Nrf2: nuclear factor erythroid 2-related factor 2; Keap1: Kelch-like ECH-associated protein 1; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; TNF-α: tumor necrosis factor alpha, IL-6: interleukin-6, IL-1β: interleukin-1β; SOD: superoxide dismutase; CAT: catalase; GPx: glutathione peroxidase; PRDX: peroxiredoxin; GCL: glutamate cysteine ligase; GST: glutathione S-transferase; NQO1: nicotinamide adenine dinucleotide phosphate quinone oxidoreductase 1; HO1: heme oxygenase-1.

Figure 2

Interplay between DUX4 and oxidative stress in FSHD. This schematic highlights the role of DUX4 in oxidative stress induction during FSHD development and progression. Abbreviations: DUX4: double homeobox 4; Nrf2: nuclear factor erythroid 2-related factor 2; ROS: reactive oxygen species; PI3K: phosphatidylinositol 3-kinase; ATK: protein kinase B; ERK: mitogen-activated protein kinase, TNF-α: tumor necrosis factor alpha; JNK: c-Jun N-terminal kinase; HIF-1: hypoxia-inducible factor 1.

Figure 3

Schematic illustration of antioxidant therapy targets in muscular dystrophies. Abbreviations: ROS: reactive oxygen species; NAC: N-acetylcysteine; MT1: metallothionein 1; MT2: metallothionein 2; GSH: glutathione; SFN: isothiocyanate sulforaphane; Nrf2: nuclear factor erythroid 2-related factor 2; MnSOD: manganese superoxide dismutase; GCS: γ-glutamylcysteine synthetase; GPx: glutathione peroxidase; SOD: superoxide dismutase.