The cell biology of disease: cellular and molecular mechanisms underlying muscular dystrophy

Abstract

The muscular dystrophies are a group of heterogeneous genetic diseases characterized by progressive degeneration and weakness of skeletal muscle. Since the discovery of the first muscular dystrophy gene encoding dystrophin, a large number of genes have been identified that are involved in various muscle-wasting and neuromuscular disorders. Human genetic studies complemented by animal model systems have substantially contributed to our understanding of the molecular pathomechanisms underlying muscle degeneration. Moreover, these studies have revealed distinct molecular and cellular mechanisms that link genetic mutations to diverse muscle wasting phenotypes.

Figure 1.

Sarcolemmal proteins and sarcomere structure. (A) The DAPC is a multimeric protein complex that connects the intracellular cytoskeleton of a myofiber to the ECM, which is composed of laminin, collagen, and other proteins. The muscle-specific laminin is composed of α2, β1, and γ1 chains. The α2 subunit directly interacts with glycosylated α-dystroglycan, which in turn interacts with the transmembrane β-dystroglycan. The dystrophin protein has four functional domains including the N-terminal, a long middle rod, cysteine-rich, and C-terminal domains. The central rod domain consists of 24 spectrin-like repeats arranged head-to-tail and interspersed by four flexible hinges. The N-terminal and the spectrin-like repeats bind to F-actin of the cytoskeleton, but not to the α-actin of thin sarcomeric filaments. The cysteine-rich domain binds to β-dystroglycan and the adjacent C-terminal domain binds to α-dystrobrevin and syntrophin. The cytolinker protein plectin binds β-dystroglycan and dystrophin and connects desmin IFs with the DAPC. Microtubules also interact with dystrophin. The four subunits of the sarcoglycan complex interact with each other and with the transmembrane protein sarcospan. The small leucine-rich repeat proteoglycan biglycan in the ECM binds to α- and γ-sarcoglycan and α-dystroglycan. Syntrophins bind to dystrophin, α-dystrobrevin, nNOS, and caveolin-3. The α7β1 integrin dimer binds laminin extracellularly and actin intracellularly via the vinculin (V) and talin (T) proteins. (B) The basic contractile unit of skeletal muscle, the sarcomere, is composed of thin and thick filaments predominantly composed of actin and myosin, respectively. Thin filaments of adjacent sarcomeres are anchored at the Z-disk, which defines the lateral borders of the sarcomere. Myosin has a long, fibrous tail and a globular head, which interacts with actin to produce muscle contraction.

Figure 2.

Dysferlin-mediated sarcolemma repair. (A) Repetitive muscle contractions often cause membrane disruption. Mitsugumin 53 (MG53; red) located on intracellular membrane-bound vesicles oligomerizes when exposed to oxidized extracellular components (gray circles) and recruits dysferlin-carrying vesicles to the injury site. Simultaneously but independently of these vesicles, intracellular annexin 6 (ANXA6) accumulates at the membrane lesion. (B) Together with dysferlin, ANXA6 sequentially recruits ANXA2 and ANXA1 to the injury site. (C) Elevated intracellular Ca²⁺ concentration facilitates fusion of intracellular vesicles with each other and with the plasma membrane through interactions between dysferlin, annexins, and other proteins at the disrupted site, rapidly forming a membrane repair patch.

Figure 3.

Primary molecular mechanisms underlying toxic RNA and toxic transcription factor–induced muscular dystrophies. (A) The expanded CUG tract within the 3′ UTR of the DMPK mRNA folds into a double-stranded hairpin structure that resembles the cognate binding site of the muscleblind-like 1 (MBNL1) protein. MBNL1 binds the expanded RNA molecules and becomes sequestered within the nucleus, resulting in loss of its normal function in RNA splicing and enhancing formation of the foci that trap the expanded RNA in the nucleus. The nuclear accumulation of this RNA disrupts RNA-processing functions in the nucleus and cytoplasm, affecting the regulation of alternative splicing and translation of many pre-mRNAs. A handful of well-studied examples are listed in the figure. Hyperphosphorylation and up-regulation of CELF1 as a result of expanded CUG repeats affect alternative splicing, translation, and mRNA stability of its target genes. (B) Unaffected individuals carry 11–100 repeats (triangles) within the D4Z4 macrosatellite on the telomeric end of chromosome 4q35. Contraction of D4Z4 repeats to <10 repeats relaxes the chromatin and induces DUX4 expression from the distal-most repeat unit (shown separately). DUX4 expressed from the nonpermissive chromosomal allele that does not contain the poly(A) signal (yellow bar) does not get polyadenylated and is unstable, whereas polyadenylated transcripts expressed from the permissive allele (red bar) are stable and translate into toxic transcription factor. Black triangles depict condensed chromatin, whereas gray triangles depict relaxed chromatin as a result of hypomethylation. SMCHD1 regulates D4Z4 methylation. In FSHD2, mutated SMCH1 fails to methylate D4Z4 and suppress DUX4 expression.