Impaired oxygen demand during exercise is related to oxidative stress and muscle function in Facioscapulohumeral Muscular Dystrophy

Abstract

Aims Facioscapulohumeral muscular dystrophy (FSHD) causes progressive muscle weakness and loss. This study aims to compare changes in quadriceps oxygenation and hemodynamics during maximal voluntary quadriceps isometric contraction (MVCQ) and to determine the relationships between these parameters and systemic oxidative stress markers and muscle structural parameters and muscle volume in patients with FSHD and healthy controls. Methods and results 17 patients with FSHD and 14 sedentary healthy controls were matched for age and physical activity level. Blood antioxidant status and stress markers were evaluated. The quadriceps tissue oxygenation index was evaluated by near infrared spectroscopy during MVCQ. Quadriceps volume was determined by magnetic resonance imaging. Quadriceps muscle samples were obtained to evaluate muscle fiber typology and mitochondria morphology by transmission electron microcopy (TEM). Groups were compared by the unpaired Student t‐test or by the non‐parametric Kruskal ‐ Wallis test in case of skewed distributions with p<0.05. Associations were assessed by Spearman correlations. Compared to controls, patients with FSHD displayed a significantly lower local O2 consumption per second that was correlated with significantly lower MVCQ and systemic oxidative stress marker levels. Although no difference in muscle typology was observed between groups, TEM showed abnormal aggregation of mitochondria near blood capillaries in FSHD muscles. Conclusions These results suggest that patients with FSHD have a lower O2 demand during MVCQ and that TOI measured by NIRS during MVC could be useful to determine the muscle oxidative capacity. Furthermore, these adaptations are related to the muscle structure reorganization linked to the occurrence of oxidative stress.

Pathomechanisms and biomarkers in facioscapulohumeral muscular dystrophy: roles of DUX4 and PAX7

“…Although symptomatic retinal vascular disease is rare (0.2–1.5% of patients) (Tawil et al , 2015 ), a degree of aberrant retinal vasculature can be detected on fluorescence angiography in up to 75% of FSHD patients, associating inversely with D4Z4 repeat length (Fitzsimons, 2011 ; Goselink et al , 2019b ). This may indicate wider vascular defects, and there is a reduced capillary density in FSHD muscle (Statland et al , 2015 ), as well as impaired muscle oxygenation (Olivier et al , 2016 ; Wilson et al , 2018 ). Sensorineural hearing loss is also a common extra‐muscular feature, with a prevalence of 12–19% (Tawil et al , 2015 ).…”

“…Thus, an increase in the glutathione disulphide:glutathione ratio drives accumulation of H 2 O 2 and related ROS promoting cell and DNA damage (Esteve et al , 1999 ). Impaired muscle oxygenation in FSHD may also contribute to ROS sensitivity (Olivier et al , 2016 ; Wilson et al , 2018 ). Other molecular mechanisms underlying oxidative stress sensitivity include p21 upregulation (Winokur et al , 2003a ), increased HIF1α (Tsumagari et al , 2011 ; Banerji et al , 2015 ; Banerji et al , 2017 ; Lek et al , 2020 ), mitochondrial dysfunction (Turki et al , 2012 ; Banerji et al , 2019 ), RAGE‐NF‐κB signalling (Macaione et al , 2007 ) and membrane repair deficits (Bittel et al , 2020 ).…”

Membrane Repair Deficit in Facioscapulohumeral Muscular Dystrophy

“…Furthermore, intact myofibers from a transgenic mouse model of FSHD demonstrated similar sarcolemmal repair deficits compared to their wild type littermates. Based on previous research demonstrating the central role of DUX4 and reduced ability of FSHD cells to handle increased oxidative stress [25,26], we showed that lowering DUX4 expression with antisense oligonucleotides, and a membrane associating antioxidant/ROS-scavenger (Trolox), significantly improved repair in FSHD myoblasts. These findings demonstrate, for the first time, that membrane repair deficits may contribute to FSHD onset and/or progression, and that this deficit could be linked to DUX4 expression and oxidative stress.…”

“…Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant neuromuscular disorder characterized by asymmetric muscle weakness, atrophy, fatty infiltration, and inflammation, typically beginning in the muscles of the face and periscapular region and progressing to the lower extremities over time [1]. In~95% of cases, disease onset is linked to a contraction in the number of 3.3 Kb, GC-rich D4Z4 repeats on chromosome 4q35 from 11-100 (average [25][26][27][28][29][30][31][32][33][34][35] in healthy individuals, to 1-11 repeats in FSHD1 [2,3]. This contraction leads to a loss of repressive histone marks, relaxation of chromatin, and DNA hypomethylation, which reverses the normal pattern of epigenetic repression of the D4Z4 locus and facilitates abnormal gene expression [3].…”

“…Chronic ROS-induced cell damage (oxidized DNA, lipid peroxides) is a central feature of FSHD that develops secondary to mitochondrial dysfunction (e.g., separation of inner and outer mitochondrial membrane, pathological swelling), and an insufficient antioxidant defense despite compensatory elevations in key antioxidant enzymes (due, in part, to the loss of antioxidative cofactors) [23][24][25][26][27]. While we previously demonstrated that carefully controlled mitochondrial ROS signaling is essential for muscle membrane repair, chronic oxidative stress (8-24 h) interferes with this process [28,29].…”