Bioenergetic Impairment in Congenital Muscular Dystrophy Type 1A and Leigh Syndrome Muscle Cells

Abstract

Skeletal muscle has high energy requirement and alterations in metabolism are associated with pathological conditions causing muscle wasting and impaired regeneration. Congenital muscular dystrophy type 1A (MDC1A) is a severe muscle disorder caused by mutations in the LAMA2 gene. Leigh syndrome (LS) is a neurometabolic disease caused by mutations in genes related to mitochondrial function. Skeletal muscle is severely affected in both diseases and a common feature is muscle weakness that leads to hypotonia and respiratory problems. Here, we have investigated the bioenergetic profile in myogenic cells from MDC1A and LS patients. We found dysregulated expression of genes related to energy production, apoptosis and proteasome in myoblasts and myotubes. Moreover, impaired mitochondrial function and a compensatory upregulation of glycolysis were observed when monitored in real-time. Also, alterations in cell cycle populations in myoblasts and enhanced caspase-3 activity in myotubes were observed. Thus, we have for the first time demonstrated an impairment of the bioenergetic status in human MDC1A and LS muscle cells, which could contribute to cell cycle disturbance and increased apoptosis. Our findings suggest that skeletal muscle metabolism might be a promising pharmacological target in order to improve muscle function, energy efficiency and tissue maintenance of MDC1A and LS patients.

Effects of metformin on congenital muscular dystrophy type 1A disease progression in mice: a gender impact study

“…Finally, we measured the expression of Pgc1 α encoding peroxisome proliferator-activated receptor gamma coactivator 1α (a key regulator of mitochondrial metabolism) that we have shown to be decreased in LAMA2-CMD patient myotubes 5 . However, expression of Pgc1 α was not altered in dy 2J /dy 2J muscles and metformin did not change its expression either (Figs 6F and 7F ).…”

“…A majority of the differentially expressed genes and proteins were found to be involved in various metabolic processes 3 , 4 . Subsequently, we demonstrated functional bioenergetic impairment with reduced mitochondrial respiration and a compensatory upregulation of glycolysis in human LAMA2-CMD muscle cells 5 . Thus, from these studies, we concluded that skeletal muscle metabolism may be a promising pharmacological target to improve muscle function in LAMA2-CMD patients.…”

Antioxidants Reduce Muscular Dystrophy in the dy2J/dy2J Mouse Model of Laminin α2 Chain-Deficient Muscular Dystrophy

“…We have previously performed transcriptional and proteomic profiling of LAMA2-CMD mouse muscles and found that a majority of the dysregulated genes and proteins are involved in various metabolic processes, indicating a metabolic crisis in LAMA2-CMD muscles [9,10]. More recently, a metabolic impairment, with reduced mitochondrial respiration and enhanced glycolysis was observed in human laminin α2-chain deficient muscle cells [11]. Insufficient mitochondrial respiration in turn, enhances the formation of reactive oxygen species (ROS), which long have been suggested to be major contributors to muscle damage in dystrophic muscles [12].…”

A Family of Laminin α2 Chain-Deficient Mouse Mutants: Advancing the Research on LAMA2-CMD

“…Mouse models for LAMA2-CMD have provided an excellent platform for studies of signaling events. Signaling cascades associated with apoptosis, inflammation, metabolism, regeneration, protein turnover, and fibrosis (GAPDH-Siah1-CBP/p300-p53, Akt, TGFβ, NFκB, p53, JAK/STAT, to mention a few) have been shown to be affected in laminin α2 chain-deficient murine muscle (Girgenrath et al, 2004(Girgenrath et al, , 2009Erb et al, 2009;Carmignac et al, 2011a,b;Kumar et al, 2011;Meinen et al, 2012;Elbaz et al, 2015;de Oliveira et al, 2014;Mehuron et al, 2014;Accorsi et al, 2015;Fontes-Oliveira et al, 2017;Gawlik et al, 2017Gawlik et al, , 2019Nunes et al, 2017;Pasteuning-Vuhman et al, 2018;Yoon et al, 2018). Additionally, microarray, RNA-sequencing and proteomic technologies were applied to study murine LAMA2-CMD dystrophic muscle and provided a global overview of the gene and protein expression changed upon laminin α2 chaindeficiency (van Lunteren et al, 2006;Hager et al, 2008;de Oliveira et al, 2014;Kemaladewi et al, 2017;Moreira Soares Oliveira et al, 2018;Yanay et al, 2019).…”