title: 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.
authors.affiliation: Unit of Muscle Biology, Department of Experimental Medical Science, Lund University, Lund, Sweden.
authors.forename: Cibely C
authors.initials: CC
authors.lastname: Fontes-Oliveira
authors.affiliation: Unit of Muscle Biology, Department of Experimental Medical Science, Lund University, Lund, Sweden.
authors.forename: Maarten
authors.initials: M
authors.lastname: Steinz
authors.affiliation: Friedrich-Baur-Institute, Department of Neurology, Ludwig-Maximilians-University of Munich, Munich, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Schneiderat
authors.affiliation: Unit of Molecular Metabolism, Department of Clinical Sciences, Lund University Diabetes Centre, Malmö University Hospital, Malmö, Sweden.
authors.forename: Hindrik
authors.initials: H
authors.lastname: Mulder
authors.affiliation: Unit of Muscle Biology, Department of Experimental Medical Science, Lund University, Lund, Sweden.
authors.forename: Madeleine
authors.initials: M
authors.lastname: Durbeej
mesh_terms: D017209:Apoptosis; D002478:Cells, Cultured; D006019:Glycolysis; D006801:Humans; D007797:Laminin / Q000235:genetics; D007888:Leigh Disease / Q000378:metabolism*; D018485:Muscle Fibers, Skeletal / Q000378:metabolism*; D009136:Muscular Dystrophies / Q000235:genetics / Q000378:metabolism*; D032446:Myoblasts / Q000378:metabolism*; D010085:Oxidative Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism
chemical_list: D007797:Laminin; C102645:laminin alpha 2; D046988:Proteasome Endopeptidase Complex