Are Antioxidants a Potential Therapy for FSHD? A Review of the Literature

Abstract

Facioscapulohumeral muscular dystrophy (FSHD) is an inherited myopathy affecting approximately 1 in 7500 individuals worldwide. It is a progressive disease characterised by skeletal muscle weakness and wasting. A genetic mutation on the 4q35 chromosome results in the expression of the double homeobox 4 gene (DUX4) which drives oxidative stress, inflammation, toxicity, and atrophy within the skeletal muscle. FSHD is characterised by oxidative stress, and there is currently no cure and a lack of therapies for the disease. Antioxidants have been researched for many years, with investigators aiming to use antioxidants therapeutically for oxidative stress-associated diseases. This has included both natural and synthetic antioxidants. The use of antioxidants in preclinical or clinical models has been largely successful with a plethora of research reporting positive results. However, when translated to clinical trials, the use of antioxidants as a therapeutic intervention for a variety of disease has been largely unsuccessful. Moreover, specifically focusing on FSHD, limited research has been conducted on the use of antioxidants as a therapy in either preclinical or clinical models. This review summarises the current state of antioxidant use in the treatment of FSHD and discusses their potential avenue for therapeutic use for FSHD patients.

Figure 1

The molecular signatures of chromosome 4 in both FSHD and healthy individuals. Healthy unaffected individuals carry 11–100 repeat units, whereas individuals with FSHD carry less than 15 repeat units (green triangles represent repeat units). Contraction of the D4Z4 repeat in FSHD results in the protein DUX4 being expressed but only in conjunction with a 4qA allele and working pLAM. Individuals with FSHD have an increased amount of hypomethylated CpGs which also contributes to the transcription of DUX4.

Figure 2

Schematic of the transcriptional cascade effect of DUX4 in which it increases sensitivity to oxidative stress, inflammation, and apoptosis; impairs skeletal muscle contraction; and results in a myoblast differentiation defect. PITX1 = pituitary homeobox 1; P53 = tumour protein 53; MyoD = myogenic differentiation.

Figure 3

A schematic of the reactions which lead to the formation of free radicals. Red text indicates free radicals. Green arrows represent lipid peroxidation, orange arrows represent the Fenton reactions, and the blue arrows represent the Haber-Weiss reactions. SOD is the enzyme superoxide dismutase, and GSSG refers to glutathione disulphide. HO₂· = hydroperoxyl radical; O₂·⁻ = superoxide radical; H₂O₂ = hydrogen peroxide; ·OH = hydroxyl radical; L· = lipid radical; LOO· = fatty acid peroxyl radical; LOOH = lipid hydroperoxide.