Abstract
Myotonic dystrophy type 1 (DM1) and 2 (DM2) are autosomal dominant degenerative neuromuscular disorders characterized by progressive skeletal muscle weakness, atrophy, and myotonia with progeroid features. Although both DM1 and DM2 are characterized by skeletal muscle dysfunction and also share other clinical features, the diseases differ in the muscle groups that are affected. In DM1, distal muscles are mainly affected, whereas in DM2 problems are mostly found in proximal muscles. In addition, manifestation in DM1 is generally more severe, with possible congenital or childhood-onset of disease and prominent CNS involvement. DM1 and DM2 are caused by expansion of (CTG•CAG)n and (CCTG•CAGG)n repeats in the 3′ non-coding region of DMPK and in intron 1 of CNBP, respectively, and in overlapping antisense genes. This critical review will focus on the pleiotropic problems that occur during development, growth, regeneration, and aging of skeletal muscle in patients who inherited these expansions. The current best-accepted idea is that most muscle symptoms can be explained by pathomechanistic effects of repeat expansion on RNA-mediated pathways. However, aberrations in DNA replication and transcription of the DM loci or in protein translation and proteome homeostasis could also affect the control of proliferation and differentiation of muscle progenitor cells or the maintenance and physiological integrity of muscle fibers during a patient’s lifetime. Here, we will discuss these molecular and cellular processes and summarize current knowledge about the role of embryonic and adult muscle-resident stem cells in growth, homeostasis, regeneration, and premature aging of healthy and diseased muscle tissue. Of particular interest is that also progenitor cells from extramuscular sources, such as pericytes and mesoangioblasts, can participate in myogenic differentiation. We will examine the potential of all these types of cells in the application of regenerative medicine for muscular dystrophies and evaluate new possibilities for their use in future therapy of DM.
Highlights
Skeletal muscle formation, growth, and maintenance in vertebrates are dynamic processes in terms of tissue differentiation, remodeling, repair, and regeneration
The focus here is on aexamination of studies related to the molecular and histomorphological problems that occur during growth, maintenance, and aging of skeletal muscles in patients with DM
The proliferating progenitor cells derived from the embryonic mesenchyme of the somite undergo different phases of myotome development. This process starts with programmed maturation accompanied by adoption of skeletal muscle fate and withdrawal from the cell cycle, giving rise to a layer of non-proliferating myoblasts that form the primary myotome beneath the dermomyotome [131, 132]
Summary
Skeletal muscle formation, growth, and maintenance in vertebrates are dynamic processes in terms of tissue differentiation, remodeling, repair, and regeneration. Patients with inherited myopathy or muscular dystrophy, a heterogeneous group of disorders for which disease etiology is rooted in the genetically abnormal pathways that control formation and physiological integrity of skeletal muscle, commonly experience progressive muscle weakness and atrophy (i.e., loss of muscle mass). The classification as a skeletal muscle dystrophy is only partially correct, as the disease has neuromuscular character and cardiac, CNS and endocrine problems are commonly involved as well [1,2,3]. The focus here is on a (re)examination of studies related to the molecular and histomorphological problems that occur during growth, maintenance, and aging of skeletal muscles in patients with DM. We will discuss possibilities to use these progenitor cells in future therapeutic strategies
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