The Impact of Mitochondrial Deficiencies in Neuromuscular Diseases

Abstract

Neuromuscular diseases (NMDs) are a heterogeneous group of acquired or inherited rare disorders caused by injury or dysfunction of the anterior horn cells of the spinal cord (lower motor neurons), peripheral nerves, neuromuscular junctions, or skeletal muscles leading to muscle weakness and waste. Unfortunately, most of them entail serious or even fatal consequences. The prevalence rates among NMDs range between 1 and 10 per 100,000 population, but their rarity and diversity pose difficulties for healthcare and research. Some molecular hallmarks are being explored to elucidate the mechanisms triggering disease, to set the path for further advances. In fact, in the present review we outline the metabolic alterations of NMDs, mainly focusing on the role of mitochondria. The aim of the review is to discuss the mechanisms underlying energy production, oxidative stress generation, cell signaling, autophagy, and inflammation triggered or conditioned by the mitochondria. Briefly, increased levels of inflammation have been linked to reactive oxygen species (ROS) accumulation, which is key in mitochondrial genomic instability and mitochondrial respiratory chain (MRC) dysfunction. ROS burst, impaired autophagy, and increased inflammation are observed in many NMDs. Increasing knowledge of the etiology of NMDs will help to develop better diagnosis and treatments, eventually reducing the health and economic burden of NMDs for patients and healthcare systems.

Linking Oxidative Stress and DNA Damage to Changes in the Expression of Extracellular Matrix Components

“…In line with this, mutations in genes encoding ECM components or molecules that bridge the ECM to the cell cytoskeleton have been described to lead to mitochondrial dysfunction ( Irwin et al, 2003 ; Millay et al, 2008 ; Shkryl et al, 2009 ; Menazza et al, 2010 ; de Oliveira et al, 2014 ; Sorato et al, 2014 ; Fontes-Oliveira et al, 2017 ; Gremminger et al, 2019 ; Kölbel et al, 2019 ), a driving force for ROS accumulation. There are several different mechanisms that can explain why mitochondria may function as an important sensor for ECM changes ( De Cavanagh et al, 2009 ), and therefore, why mitochondrial dysfunction is a hallmark of muscular dystrophies ( Cantó-Santos et al, 2020 ). ECM glycoproteins, including laminins and fibronectin, have been shown to promote mitochondrial function via integrin-focal adhesion kinase (FAK) signaling, which culminates in the translocation of phosphorylated STAT3 to the mitochondria ( Visavadiya et al, 2016 ; Figure 3B ).…”

Network Pharmacology/Metabolomics-Based Validation of AMPK and PI3K/AKT Signaling Pathway as a Central Role of Shengqi Fuzheng Injection Regulation of Mitochondrial Dysfunction in Cancer-Related Fatigue

“…One primary feature of CRF is skeletal muscular and mitochondrial dysfunction. The energy metabolism disorders of CRF mainly result from mitochondrial dysfunction and apoptotic skeletal muscular cells, which are caused by impaired energy production or ATP longitudinal depletions [20][21][22]. The mitochondrial abnormalities which are associated with energy metabolism disorders of CRF include the mitochondrial membranes integrity loss, translocator protein oxidative corruption, abnormal muscle mitochondrial morphologies, and defective aerobic metabolism, or both [23,24].…”

β-Glucans as Dietary Supplement to Improve Locomotion and Mitochondrial Respiration in a Model of Duchenne Muscular Dystrophy

“…Upon treatment with 1,3-1,6 β-glucans, dystrophic larvae travelled longer distances at higher velocity than non-dystrophic ones. This result suggests that 1,3-1,6 β-glucans improves locomotor activity and mitochondrial respiration despite the impaired muscular and mitochondrial function typical of muscular dystrophy, by counteracting muscle dysregulations in dystrophic larvae [ 69 ]. Similar evidence has been already reported by [ 49 , 50 , 51 , 52 ] for compounds different from β-glucans.…”