Skeletal and Cardiac Muscle Disorders Caused by Mutations in Genes Encoding Intermediate Filament Proteins

Abstract

Intermediate filaments are major components of the cytoskeleton. Desmin and synemin, cytoplasmic intermediate filament proteins and A-type lamins, nuclear intermediate filament proteins, play key roles in skeletal and cardiac muscle. Desmin, encoded by the DES gene (OMIM *125660) and A-type lamins by the LMNA gene (OMIM *150330), have been involved in striated muscle disorders. Diseases include desmin-related myopathy and cardiomyopathy (desminopathy), which can be manifested with dilated, restrictive, hypertrophic, arrhythmogenic, or even left ventricular non-compaction cardiomyopathy, Emery-Dreifuss Muscular Dystrophy (EDMD2 and EDMD3, due to LMNA mutations), LMNA-related congenital Muscular Dystrophy (L-CMD) and LMNA-linked dilated cardiomyopathy with conduction system defects (CMD1A). Recently, mutations in synemin (SYNM gene, OMIM *606087) have been linked to cardiomyopathy. This review will summarize clinical and molecular aspects of desmin-, lamin- and synemin-related striated muscle disorders with focus on LMNA and DES-associated clinical entities and will suggest pathogenetic hypotheses based on the interplay of desmin and lamin A/C. In healthy muscle, such interplay is responsible for the involvement of this network in mechanosignaling, nuclear positioning and mitochondrial homeostasis, while in disease it is disturbed, leading to myocyte death and activation of inflammation and the associated secretome alterations.

Keywords: cardiomyopathy; desmin; desminopathy; lamin A/C; mechanosignaling; muscular laminopathies; nuclear positioning; secretome; synemin.

Figure 1

Schematic representation of intermediate filament proteins desmin, lamin A/C and synemin distribution in myocardium. Desmin connects the Z-disks with the intercalated disks, mitochondria, lysosomes (not shown here) and the nuclear periphery. Synemin binds desmin at costameres (not shown here), the membrane units at the Z-disks. Desmoplakin connects desmin to plakoglobin at the intercalated disks. Nesprin 3 binds desmin at the nuclear periphery of cardiomyocytes. Lamin A/C is localized at the nuclear lamina, beneath the inner nuclear membrane and connects to nesprin 3 in the LINC complex (see text). Lamin A/C is also localized in the nucleoplasm. Desmin can transiently enter the nucleus (dotted yellow lines) in cardiac stem cells and interact with transcription factors [16]. In skeletal muscle, similar interactions are established at the Z-disks, mitochondria, lysosomes and costameres between desmin, lamin A/C or synemin and their binding partners [14]. Scale bar, approx. 1 μm.

Figure 2

Schematic representation of α-Synemin, β-Synemin, L-Synemin, Desmin, Lamin A and Lamin C protein structure. Each intermediate filament protein has: a head domain (purple); a rod domain including coil1A (1A), coil 1B (1B), a linker domain called L12 (small green box) and coil 2 (2); a tail domain (blue), which can be of variable length even in protein isoforms. Lamin A and C have a globular domain (orange) in their tail. Prelamin A-specific tail with C-terminal CAAX box (red) is also represented. Prelamin A tail is removed upon protein post-translational processing to yield mature Lamin A. α-Synemin, β-, Synemin and L-Synemin are splicing products of SYNM gene, Desmin is the product of DES gene, Lamin A and C are splicing products of LMNA gene. The number of amino acids is indicated at the C-terminus for each protein.

Figure 3

Muscle districts affected in striated muscle disorders caused by mutations in intermediate filament proteins. In the upper row, gene names causative of each group of neuromuscular disorders are indicated (SYNM, DES, LMNA). In the case of LMNA-related disorders, sites affected by contractures are also indicated. Achilles tendon contractures may occur, but are infrequent in desminopathy, thus they have not been indicated in the picture.

Figure 4

T1 weighted muscle MRI at thigh level in LMNA (A) and DES (B) mutated patients. (A) Marked fatty infiltration of the vasti (arrows) with sparing of the rectus femoris (asterisk) and of posterior compartment. (B) Marked fatty changes in semitendinosus, sartorius and gracilis (arrows) with relative sparing of long head of biceps femoris and semimembranosus (asterisks).

Figure 5

Nucleoplasmic localization of lamin A/C is increased in the nuclei of desmin deficient cardiomyocytes. Electron microscopic analysis of cardiac tissue sections from wild-type and desmin-null mice, immunogold-labeled for lamin A/C. Lamin A/C-bound gold particles are evident at the nuclear periphery (arrows) of the wild-type nucleus and appear reduced in desmin-null nucleus. Nucleoplasmic accumulation of lamin A/C-bound gold particles is observed in the desmin-null nucleus (arrowheads). (n, nucleus; cyt, cytoplasm). Scale bar, 100 nm.

Figure 6

Lamin A/C and desmin potential pathogenetic role in muscle cells. Intracellular structures involved in lamin A/C and/or desmin-related functions and pathogenetic mechanisms related to each function are schematically represented. Lamin A/C and desmin are represented as dark red filaments. Desmin filaments connect all represented organelles and structures in skeletal or cardiac muscle (intercalated disks specifically in the heart). Each box refers to the adjacent structure. Pathogenetic events are written in bold characters in each box. Downstream of all pathogenetic events, aberrant inflammatory response and secretome defects contribute to disease progression (lower right box).