Frontiers in Aging Neuroscience (Jul 2015)

Muscle wasting in myotonic dystrophies: a model of premature aging.

  • Alba Judith eMateos-Aierdi,
  • Alba Judith eMateos-Aierdi,
  • María eGoicoechea Bianchi,
  • María eGoicoechea Bianchi,
  • Ana eAiastui,
  • Ana eAiastui,
  • Roberto eFernández-Torrón,
  • Roberto eFernández-Torrón,
  • Roberto eFernández-Torrón,
  • Mikel eGarcía-Puga,
  • Ander eMatheu,
  • Adolfo eLópez De Munain,
  • Adolfo eLópez De Munain,
  • Adolfo eLópez De Munain,
  • Adolfo eLópez De Munain

DOI
https://doi.org/10.3389/fnagi.2015.00125
Journal volume & issue
Vol. 7

Abstract

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Myotonic dystrophy type I (DM1 or Steinert’s disease) and type II (DM2) are multisystem disorders of genetic origin. Progressive muscular weakness, atrophy and myotonia are the most prominent neuromuscular features of these diseases, and 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)n triplet expansion in the 3’ untranslated region of the DMPK gene, whereas (CCTG)n repeats in the first intron of the 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.

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