Satellite cell dysfunction contributes to the progressive muscle atrophy in myotonic dystrophy type 1

• Published in: Neuropathology and applied neurobiology Vol. 35; no. 6; pp. 603 - 613
• Main Authors: Thornell, L.-E., Lindstöm, M., Renault, V., Klein, A., Mouly, V., Ansved, T., Butler-Browne, G., Furling, D.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-11-2009; Blackwell
• Subjects: Adult; atrophy; Biological and medical sciences; Cell Count; Cell Proliferation; Cells, Cultured; CTG repeats; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Female; Humans; Immunohistochemistry; Male; Medical sciences; Medicin och hälsovetenskap; Middle Aged; muscle; Muscle, Skeletal - pathology; Muscle, Skeletal - physiopathology; Muscular Atrophy - genetics; Muscular Atrophy - pathology; Muscular Atrophy - physiopathology; Myotonic Dystrophy - genetics; Myotonic Dystrophy - pathology; Myotonic Dystrophy - physiopathology; myotonic dystrophy type 1; Myotonin-Protein Kinase; Neurology; Protein-Serine-Threonine Kinases - genetics; Regeneration - physiology; satellite cells; Satellite Cells, Skeletal Muscle - pathology; Satellite Cells, Skeletal Muscle - physiology; Severity of Illness Index; Telomere - physiology; Trinucleotide Repeat Expansion; Young Adult; Neuromuscular diseases; Nervous system diseases; CTG repeats; Myotonia; Amyotrophy; myotonic dystrophy type 1; Genetic disease; Atrophy; Striated muscle disease; Myotonic dystrophy; Dysfunction; Muscle; Satellite cell; satellite cells
• ISSN: 0305-1846; 1365-2990; 1365-2990
• DOI: 10.1111/j.1365-2990.2009.01014.x

Aims: Myotonic dystrophy type 1 (DM1), one of the most common forms of inherited neuromuscular disorders in the adult, is characterized by progressive muscle weakness and wasting leading to distal muscle atrophy whereas proximal muscles of the same patients are spared during the early phase of the disease. In this report, the role of satellite cell dysfunction in the progressive muscular atrophy has been investigated. Methods: Biopsies were obtained from distal and proximal muscles of the same DM1 patients. Histological and immunohistological analyses were carried out and the past regenerative history of the muscle was evaluated. Satellite cell number was quantified in vivo and proliferative capacity was determined in vitro.Results: The size of the CTG expansion was positively correlated with the severity of the symptoms and the degree of muscle histopathology. Marked atrophy associated with typical DM1 features was observed in distal muscles of severely affected patients whereas proximal muscles were relatively spared. The number of satellite cells was significantly increased (twofold) in the distal muscles whereas very little regeneration was observed as confirmed by telomere analyses and developmental MyHC staining (0.3–3%). The satellite cells isolated from the DM1 distal muscles had a reduced proliferative capacity (36%) and stopped growing prematurely with telomeres longer than control cells (8.4 vs. 7.1 kb), indicating that the behaviour of these precursor cells was modified. Conclusions: Our results indicate that alterations in the basic functions of the satellite cells progressively impair the muscle mass maintenance and/or regeneration resulting in gradual muscular atrophy.