Premature senescence in primary muscle cultures of myotonic dystrophy type 2 is not associated with p16 induction

Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are multisystemic disorders linked to two different genetic loci and characterized by several features including myotonia, muscle weakness and atrophy, cardiac dysfunctions, cataracts and insulin-resistance. In both forms, expanded nucleotide sequences cause the accumulation of mutant transcripts in the nucleus deregulating the activity of some RNAbinding proteins and providing an explanation for the multisystemic phenotype of DM patients. However this pathogenetic mechanism does not explain some histopathological features of DM skeletal muscle like muscle atrophy. It has been observed that DM muscle shares similarities with the ageing muscle, where the progressive muscle weakness and atrophy is accompanied by a lower regenerative capacity possibly due to the failure in satellite cells activation. The aim of our study is to investigate if DM2 satellite cell derived myoblasts exhibit a premature senescence as reported for DM1 and if alterations in their proliferation potential and differentiation capabilities might contribute to some of the histopathological features observed in DM2 muscles. Our results indicate that DM myoblasts have lower proliferative capability than control myoblasts and reach in vitro senescence earlier than controls. Differentely from DM1, the p16 pathway is not responsible for the premature growth arrest observed in DM2 myoblasts which stop dividing with telomeres shorter than controls. During in vitro senescence, a progressive decrease in fusion index is observable in both DM and control myotubes with no significant differences between groups. Moreover, myotubes obtained from senescent myoblasts appear to be smaller than those from young myoblasts. Taken together, our data indicate a possible role of DM2 premature myoblast senescence in skeletal muscle histopathological alterations i.e., dystrophic changes and type 2 fibre atrophy.

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Reduction of Cellular Nucleic Acid Binding Protein Encoded by a Myotonic Dystrophy Type 2 Gene Causes Muscle Atrophy

Molecular and Cellular Biology ◽

10.1128/mcb.00649-17 ◽

2018 ◽

Vol 38 (14) ◽

Cited By ~ 6

Author(s):

Christina Wei ◽

Lauren Stock ◽

Christiane Schneider-Gold ◽

Claudia Sommer ◽

Nikolai A. Timchenko ◽

...

Keyword(s):

Skeletal Muscle ◽

Nucleic Acid ◽

Myotonic Dystrophy ◽

Muscle Atrophy ◽

Myotonic Dystrophy Type ◽

Nucleic Acid Binding ◽

Myotonic Dystrophy Type 2 ◽

Nucleic Acid Binding Protein ◽

Acid Binding Protein

ABSTRACT Myotonic dystrophy type 2 (DM2) is a neuromuscular disease caused by an expansion of intronic CCTG repeats in the CNBP gene, which encodes a protein regulating translation and transcription. To better understand the role of cellular nucleic acid binding protein (CNBP) in DM2 pathology, we examined skeletal muscle in a new model of Cnbp knockout (KO) mice. This study showed that a loss of Cnbp disturbs myofibrillar sarcomeric organization at birth. Surviving homozygous Cnbp KO mice develop muscle atrophy at a young age. The skeletal muscle phenotype in heterozygous Cnbp KO mice was milder, but they developed severe muscle wasting at an advanced age. Several proteins that control global translation and muscle contraction are altered in muscle of Cnbp KO mice. A search for CNBP binding proteins showed that CNBP interacts with the α subunit of the dystroglycan complex, a core component of the multimeric dystrophin-glycoprotein complex, which regulates membrane stability. Whereas CNBP is reduced in cytoplasm of DM2 human fibers, it is a predominantly membrane protein in DM2 fibers, and its interaction with α-dystroglycan is increased in DM2. These findings suggest that alterations of CNBP in DM2 might cause muscle atrophy via CNBP-mediated translation and via protein-protein interactions affecting myofiber membrane function.

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Overexpression of CUGBP1 in Skeletal Muscle from Adult Classic Myotonic Dystrophy Type 1 but Not from Myotonic Dystrophy Type 2

PLoS ONE ◽

10.1371/journal.pone.0083777 ◽

2013 ◽

Vol 8 (12) ◽

pp. e83777 ◽

Cited By ~ 18

Author(s):

Rosanna Cardani ◽

Enrico Bugiardini ◽

Laura V. Renna ◽

Giulia Rossi ◽

Graziano Colombo ◽

...

Keyword(s):

Skeletal Muscle ◽

Myotonic Dystrophy ◽

Myotonic Dystrophy Type 1 ◽

Myotonic Dystrophy Type ◽

Myotonic Dystrophy Type 2

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Cardiac and skeletal muscle involvement in myotonic dystrophy type 2 (DM2): A quantitative31P-MRS and MRI study

Muscle & Nerve ◽

10.1002/mus.20156 ◽

2004 ◽

Vol 30 (5) ◽

pp. 636-644 ◽

Cited By ~ 19

Author(s):

Christiane Schneider-Gold ◽

Meinrad Beer ◽

Herbert Köstler ◽

Stefan Buchner ◽

Jörn Sandstede ◽

...

Keyword(s):

Skeletal Muscle ◽

Myotonic Dystrophy ◽

Myotonic Dystrophy Type ◽

Myotonic Dystrophy Type 2 ◽

Muscle Involvement ◽

Mri Study ◽

Skeletal Muscle Involvement

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Myotonic dystrophy-2: Unusual phenotype due to a small CCTG-expansion

Balkan Journal of Medical Genetics ◽

10.2478/bjmg-2018-0024 ◽

2018 ◽

Vol 21 (2) ◽

pp. 39-43

Author(s):

J Finsterer ◽

C Stöllberger ◽

A Reining-Festa ◽

M Loewe-Grgurin ◽

M Gencik

Keyword(s):

Myotonic Dystrophy ◽

Muscle Weakness ◽

Factor V Leiden ◽

Myotonic Dystrophy Type ◽

Multisystem Disease ◽

Myotonic Dystrophy Type 2 ◽

Factor V Leiden Mutation ◽

Endocrine Organs ◽

Vesico Ureteral Reflux

Abstract Myotonic dystrophy type 2 (MD2) is a multisystem disease, predominantly affecting the proximal limb muscles, eyes, endocrine organs, heart and intestines. Longterm asymptomatic creatine kinase (hyper-CKemia) of more than 20 years duration, in association with hyperlipidemia and diabetes, as a manifestation of MD2 has not been reported. A 52-year-old female with a history of hyper-CKemia since the age of 32 years associated with diabetes, hyperlipidemia and hyperuricemia, developed anginal chest pain and proximal muscle weakness together with clinical myotonia when opening the fists at age 51 years. Examination revealed a left anterior hemiblock, sensorimotor neuropathy, extensive myotonic discharges on needle electromyography (EMG) and a CCTG-expansion of 134 bp on the ZNF9 gene. The family history was positive for hyper-CKemia and muscle weakness. In addition, over the previous years, she had developed vesico-ureteral reflux, cutaneous melanoma, renal cysts, cervix dysplasias, thrombocytosis, cataracts, arterial hypertension, heterozygous Factor V Leiden mutation, cholecystolithiasis, multiple ovarial cysts and vitamin D deficiency. Asymptomatic, long-term hyper-CKemia in association with multisystem disease should raise the suspicion of a MD2. Rare manifestations of MD2 may be thrombocytosis, hyperuricemia, vesico-ureteral reflux, gallstones, hypertension and cyst formation. In patients with asymptomatic hyper-CKemia, needle EMG should be considered. Myotonic dystrophy type 2 may take a mild course over many years if the CCTG-expansion is short.

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