title: Muscle wasting in myotonic dystrophies: a model of premature aging.
abstract: Myotonic dystrophy type 1 (DM1 or Steinert's disease) and type 2 (DM2) are multisystem disorders of genetic origin. Progressive muscular weakness, atrophy and myotonia are the most prominent neuromuscular features of these diseases, while other clinical manifestations such as cardiomyopathy, insulin resistance and cataracts are also common. From a clinical perspective, most DM symptoms are interpreted as a result of an accelerated aging (cataracts, muscular weakness and atrophy, cognitive decline, metabolic dysfunction, etc.), including an increased risk of developing tumors. From this point of view, DM1 could be described as a progeroid syndrome since a notable age-dependent dysfunction of all systems occurs. The underlying molecular disorder in DM1 consists of the existence of a pathological (CTG) triplet expansion in the 3' untranslated region (UTR) of the Dystrophia Myotonica Protein Kinase (DMPK) gene, whereas (CCTG)n repeats in the first intron of the Cellular Nucleic acid Binding Protein/Zinc Finger Protein 9 (CNBP/ZNF9) gene cause DM2. The expansions are transcribed into (CUG)n and (CCUG)n-containing RNA, respectively, which form secondary structures and sequester RNA-binding proteins, such as the splicing factor muscleblind-like protein (MBNL), forming nuclear aggregates known as foci. Other splicing factors, such as CUGBP, are also disrupted, leading to a spliceopathy of a large number of downstream genes linked to the clinical features of these diseases. Skeletal muscle regeneration relies on muscle progenitor cells, known as satellite cells, which are activated after muscle damage, and which proliferate and differentiate to muscle cells, thus regenerating the damaged tissue. Satellite cell dysfunction seems to be a common feature of both age-dependent muscle degeneration (sarcopenia) and muscle wasting in DM and other muscle degenerative diseases. This review aims to describe the cellular, molecular and macrostructural processes involved in the muscular degeneration seen in DM patients, highlighting the similarities found with muscle aging.
authors.affiliation: Neuroscience Area, Biodonostia Health Research Institute San Sebastián, Spain ; CIBERNED, Instituto Carlos III, Ministerio de Economía y Competitividad Madrid, Spain.
authors.forename: Alba Judith
authors.initials: AJ
authors.lastname: Mateos-Aierdi
authors.affiliation: Neuroscience Area, Biodonostia Health Research Institute San Sebastián, Spain ; CIBERNED, Instituto Carlos III, Ministerio de Economía y Competitividad Madrid, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Goicoechea
authors.affiliation: CIBERNED, Instituto Carlos III, Ministerio de Economía y Competitividad Madrid, Spain ; Cell Culture Platform, Biodonostia Health Research Institute, San Sebastián Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Aiastui
authors.affiliation: Neuroscience Area, Biodonostia Health Research Institute San Sebastián, Spain ; CIBERNED, Instituto Carlos III, Ministerio de Economía y Competitividad Madrid, Spain ; Department of Neurology, Hospital Universitario Donostia, San Sebastián Spain.
authors.forename: Roberto
authors.initials: R
authors.lastname: Fernández-Torrón
authors.affiliation: Oncology Area, Biodonostia Health Research Institute San Sebastián, Spain.
authors.forename: Mikel
authors.initials: M
authors.lastname: Garcia-Puga
authors.affiliation: Oncology Area, Biodonostia Health Research Institute San Sebastián, Spain.
authors.forename: Ander
authors.initials: A
authors.lastname: Matheu
authors.affiliation: Neuroscience Area, Biodonostia Health Research Institute San Sebastián, Spain ; CIBERNED, Instituto Carlos III, Ministerio de Economía y Competitividad Madrid, Spain ; Department of Neurology, Hospital Universitario Donostia, San Sebastián Spain ; Department of Neuroscience, Universidad del País Vasco UPV-EHU San Sebastián, Spain.
authors.forename: Adolfo
authors.initials: A
authors.lastname: López de Munain
keywords: aging; muscle wasting; myotonic dystrophy; sarcopenia; satellite cells