ReviewStriated muscle laminopathies
Introduction
LMNA encodes A-type lamins, intermediate filaments of the nucleus, ubiquitously expressed in differentiated cells. Together with B-type lamins and associated nuclear envelope (NE) proteins, they form the nuclear lamina, a meshwork underlying the inner NE. Four A-type lamins are produced by alternative splicing of LMNA. Lamins A and C, the major isoforms, are expressed in all committed cells [1]. Lamins A and C (henceforth referred to as lamin A/C) are identical for their first 566 amino acids, but are distinct at their C-terminal domains (Fig. 1). Lamin C has six unique C-terminal amino acids while lamin A is synthesized as a precursor, named prelamin A, which has 98 unique C-terminal amino acids. Prelamin A is farnesylated on the cysteine residue of a C-terminal CaaX box, i.e. CSIM, and is endoproteolytically processed by the ZMPSTE24 (zinc metalloprotease Ste24 homologue) protease to yield mature lamin A, which lacks the last 18 amino acids. Lamin A/C dimerizes and further assembles to form head-to-tail polymers, which associate laterally to form lamin filaments. Lamins A and C are also found sparsely in the nucleoplasm and may have multiple functions by association with chromatin, nuclear histones and various transcription factors [2].
Since the first description of a LMNA non-sense mutation associated with Emery–Dreifuss muscular dystrophy, EDMD [3], a growing number of publications have reported LMNA mutations associated with different clinical entities, commonly named laminopathies [2], [4]. These laminopathies can be subdivided in 4 distinct groups, depending on the affected tissue: (1) striated muscles, (2) adipose tissue, (3) nervous system, and (4) accelerated aging syndrome, the later affecting tissues in a systemic manner.
This review focuses on the elucidation of the role of the lamin A/C and the pathophysiological mechanisms in striated muscles through the analysis of knock-out (KO) and knock-in (KI) mouse models, as well as the current and potentially future treatments for these different striated muscle laminopathies.
Section snippets
LMNA-related striated muscle disorders
In 1999, Bonne and co-workers have identified the first LMNA mutation in a large family with EDMD [3]. EDMD is characterized by (1) early development of contractures, mainly affecting Achilles’ tendons, the elbows and the spine, (2) slowly progressive muscle atrophy and weakness, first affecting humero-peroneal muscles, and (3) the development of cardiac dilation, with cardiac conduction defects and/or arrhythmias, often leading to cardiac sudden death [5].
Since, LMNA mutations have been
Mouse models for striated muscle laminopathies
Over the years, numerous studies have reported that A-type lamins provide structural support to the nucleus, maintenance of nuclear architecture, nuclear migration, and apoptosis, and also take part in chromatin organization and epigenetics, transcription, cell cycle regulation, cell development and differentiation [10]. To study the role of lamin A/C in skeletal and cardiac muscles, and to understand the pathophysiological processes induced by LMNA mutations, several mouse models have been
Current care of patients with striated muscle laminopathies
Currently, no specific treatment exists for striated muscle laminopathies. However, supportive care has been proposed to patients to (i) preserve muscle activity, (ii) provide functional ability, and (iii) impact on life expectancy. Concerning the contractures, Achilles tenotomy and surgical intervention of the neck and spine with internal fixation of rods can help to maintain ambulation. Bracing and orthopedic procedures are also used [88]. Still, cardiac involvement remains the most
Concluding remarks
Since the description of the first LMNA mutations in 1999, lamins A/C have been implicated in an increasing number of functions. While first described as static scaffolding proteins of the nucleus, they are now seen as dynamic proteins involved in the organization of the chromatin, in the regulation of the transcription, and in the adaptation of the cells in mechanically challenging environment. The use of animal models has led to the identification of several signaling pathways that are
Acknowledgments
The authors thank Marie-Elodie Cattin for help with preparation of Fig. 2. This work was financially supported by the Institut National de la Santé et de la Recherche Médicale; the Université Pierre et Marie Curie Paris 06, the Centre National de la Recherche Scientifique; the COST action BM1002 (Nanonet), and the Association Française contre les Myopathies.
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