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.
Highlights
Myotonic dystrophy type 1 (DM1), known as Steinert’s disease (OMIM: 160900), is a dominantly inherited multisystem disease
In vitro experiments performed with human satellite cells have confirmed this fact. These findings show that age-dependent systemic factors act on the regenerative potential of satellite cells (Carlson and Conboy, 2007; Carlson et al, 2009)
Myotonic dystrophies represent a new paradigm of how a genetically determined disease initiates a cascade of events that lead to a wide variety of symptoms that resemble the multisystem involvement induced by aging
Summary
Myotonic dystrophy type 1 (DM1), known as Steinert’s disease (OMIM: 160900), is a dominantly inherited multisystem disease. Consistent with this, congenital and childhood-onset forms of DM2 are absent, and the disease phenotype ranges from early adult-onset severe forms to very late-onset mild forms (Day et al, 2003). The prevalence of this disorder has yet to be clearly defined but it is estimated to be similar to DM1 in Northern European Countries (Udd and Krahe, 2012). One of the most severely affected tissues in these diseases, may age prematurely in DM patients, mimicking sarcopenia, known as the age-related loss of muscle mass and function (Evans and Campbell, 1993; Fielding et al, 2011). The causes of sarcopenia have not as yet been accurately determined, several age-related factors, such as muscle disuse, nutritional deficiencies, hormonal changes and insulin resistance could notably contribute to its onset
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