ANRV295-PM02-04 ARI 13 December 2006 2:57 Muscle Diseases: The Muscular Dystrophies Elizabeth M. McNally and Peter Pytel Department of Medicine, Section of Cardiology, University of Chicago, Chicago, Illinois 60637; email: [email protected] Department of Pathology, University of Chicago, Chicago, Illinois 60637; email: [email protected] Annu. Rev. Pathol. Mech. Dis. 2007. Key Words 2:87–109 myotonia, sarcopenia, muscle regeneration, dystrophin, lamin A/C, The Annual Review of Pathology: Mechanisms of Disease is online at nucleotide repeat expansion pathmechdis.annualreviews.org Abstract by Drexel University on 01/13/13. For personal use only. This article’s doi: 10.1146/annurev.pathol.2.010506.091936 Dystrophic muscle disease can occur at any age. Early- or childhood- onset muscular dystrophies may be associated with profound loss Copyright c 2007 by Annual Reviews. All rights reserved of muscle function, affecting ambulation, posture, and cardiac and respiratory function. Late-onset muscular dystrophies or myopathies 1553-4006/07/0228-0087$20.00 Annu. Rev. Pathol. Mech. Dis. 2007.2:87-109. Downloaded from www.annualreviews.org may be mild and associated with slight weakness and an inability to increase muscle mass. The phenotype of muscular dystrophy is an endpoint that arises from a diverse set of genetic pathways. Genes associated with muscular dystrophies encode proteins of the plasma membrane and extracellular matrix, and the sarcomere and Z band, as well as nuclear membrane components. Because muscle has such distinctive structural and regenerative properties, many of the genes implicated in these disorders target pathways unique to muscle or more highly expressed in muscle. This chapter reviews the basic structural properties of muscle and genetic mechanisms that lead to myopathy and muscular dystrophies that affect all age groups. 87 ANRV295-PM02-04 ARI 13 December 2006 2:57 MUSCLE STRUCTURE organized, containing chains of sarcomeres that run parallel to the length of the myofiber. The basic cellular unit of voluntary mus- Electron-dense Z bands define the borders Muscular cle is the myofiber. Myofibers are elongated, of each sarcomere, and individual sarcomeres dystrophy: multinucleate cells. During development and are composed of actin-containing thin fila- genetically linked regeneration, myofibers arise from the fusion muscle disease ments and myosin-containing thick filaments of singly nucleated myoblasts to form myo- characterized by (Figure 2). The heavy chain of myosin hy- fibers. Individual myofibers are encased in an progressive drolyzes ATP to provide the energy for mus- destruction of endomysial sheath of connective tissue, and cle contraction. The rate at which myosin hy- muscle tissue groups of myofibers are encased in epimysial drolyzes ATP is proportional to the speed of Sarcomere: basic connective tissue (Figure 1). The ends of muscle contraction. Slow type I and fast type functional unit of myofibers form myotendinous junctions, a II fibers express different myosin isoforms and muscle contraction specialized attachment for bony insertion that consisting of actin, can be distinguished by enzyme histochem- can withstand considerable force. The cyto- myosin, and istry in the ATPase reaction (Figure 1d ). The associated proteins plasm of each individual myofiber is highly by Drexel University on 01/13/13. For personal use only. Annu. Rev. Pathol. Mech. Dis. 2007.2:87-109. Downloaded from www.annualreviews.org Figure 1 Normal muscle histology. (a) Low-power H&E-stained cross section of normal skeletal muscle showing the organization of myofibers into fascicles separated by epimysial connective tissue. Overall, there is little variation in myofiber size. (b) A high-power H&E-stained cross section of normal skeletal muscle. The myofiber nuclei are located peripherally, just below the sarcolemmal membrane. Only thin strands of connective tissue separate individual myofibers within each of the three depicted fascicles. (c)A high-power H&E-stained longitudinal section of normal muscle shows cross striation, which is evidence of the highly organized cytoskeletal architecture of the myofiber. (d ) The ATPase reaction can distinguish fiber types. At the pH shown here (pH 9.4), type I fibers are light and type II fibers are dark. The checkerboard pattern reflects the normal fiber-type distribution. 88 McNally · Pytel ANRV295-PM02-04 ARI 13 December 2006 2:57 fiber type is determined by the innervating motor neuron in the spinal cord. The motor unit is the functional unit of one motor neu- ron and all the myofibers innervated by it. Several groups of muscle diseases present as weakness, cramping, or muscle pain. These include the congenital myopathies, the mus- cular dystrophies, myotonic disorders, storage diseases, mitochondrial diseases, and inflam- matory myopathies. These primary muscle diseases are distinct from neuropathic diseases and disorders of neuromuscular transmission. This review focuses on myopathies arising from defects of cytoskeletal, sarcomeric, and membrane-associated proteins of the plasma membrane and the nucleus (Table 1). Histor- ically, the diseases that fall into this group were classified on the basis of features such as the pattern of inheritance, the age of disease on- set, and the primarily affected muscle groups. The increasing ability to link these entities to specific genetic defects has greatly increased our understanding of these diseases. MUSCLE DEGENERATION AND REGENERATION Muscle damage typically takes the form of my- ofiber necrosis and regeneration (Figure 3). This process can be segmental, involving only a part of an individual myofiber. The necrosis by Drexel University on 01/13/13. For personal use only. is associated with membrane damage and leak- Figure 2 age of cytoplasmic proteins, such as creatine kinase (CK) and lactate dehydrogenase, that Transmission electron micrograph and schematic representation of a sarcomere, the basic functional contraction unit in skeletal and cardiac can serve as serum markers of muscle dam- muscle. The A band (anisotropic as seen under polarized light) marks the age. The basement membrane of the necrotic extent of the thick myosin filaments and is indicated by the green box in the Annu. Rev. Pathol. Mech. Dis. 2007.2:87-109. Downloaded from www.annualreviews.org fiber remains as a scaffold for the regener- schematic diagram. The thin actin filaments are anchored at the Z disc. ative process. Muscle is highly regenerative. The area where the thin filaments do not overlap with the thick filaments is The regenerative process occurs with the or- the I band (isotropic as seen under polarized light). The membrane overlying the sarcomere is also shown. ganization of necrotic cytoplasmic debris by inflammatory cells. Depending on the degree of damage, the time course of muscle regener- indicating mitotic activity. These two fea- ation occurs over one to three weeks. Mature tures, the mitotic activity and the location be- muscle contains mononuclear cells that re- tween the plasma membrane and the basal side between the basement membrane and lamina, were used to define muscle satellite the plasma membrane or sarcolemma of each cells (1). Experimental evidence supports that myofiber. The nuclei of these mononuclear the origin of the satellite cell is the myotome cells selectively take up bromodeoxyuridine, (2), but additional evidence suggests that www.annualreviews.org • The Muscular Dystrophies 89 ANRV295-PM02-04 ARI 13 December 2006 2:57 Table 1 Summary of different genes or these nuclei will assume a peripheral position gene products and the type of muscle near the sarcolemma, as is characteristic of the disease with which they associate mature myofiber. Sarcolemma: the specialized plasma Gene product (gene) Disease Because most muscle disease involves membrane of the Laminin α2(LAMA2) CMD myofiber damage or degeneration, regenera- individual myofibers Integrin α7(ITGA7 ) CMD tion is a feature of all muscle disease. Although in skeletal muscle Fukutin (FCMD) CMD central nucleation is seen in normal muscle Satellite cell: pool POMGnT1 CMD fiber, an increase in the number of centrally of localized tissue POMT1 WWS nucleated myofibers may indicate an ongoing stem cells in the FKRP CMD, LGMD degenerative or necrotic process. The muscle skeletal muscle LARGE important for its biopsy, viewed perpendicular to the long axis Dystrophin (DYS ) DMD development and of the myofiber, remains the gold standard for α-sarcoglycan ( ) LGMD regenerative SGCA evaluating muscle disease. The main muscle β-sarcoglycan (SGCB ) LGMD potential biopsy changes found in myopathic diseases γ-sarcoglycan (SGCG ) LGMD CMD: congenital are the presence of necrotic myofibers and δ-sarcoglycan (SGCD) LGMD muscular dystrophy Dysferlin (DYSF ) LGMD regenerative myofibers. Necrotic myofibers Calpain-3 (CAPN3 ) LGMD contain variable amounts of amorphous cel- Caveolin-3 (CAV3) LGMD, RMD lular debris, inflammatory cells, and satellite E3-ubiquitin ligase LGMD cells. Regenerative myofibers are character- (TRIM 32) ized by their enlarged nucleus and basophilic Telethonin LGMD RNA-rich cytoplasm. After the reconstitution Titin LGMD of the sarcomeric myofiber architecture, the Myotilin LGMD myofiber nuclei maintain a centralized posi- Lamin A/C ( ) LGMD, EDMD LMNA tion away from their normal subsarcolemmal Emerin (EMD) EDMD location for several weeks. In addition, myo- Color coding reveals those genetic defects that are pathic diseases also show an increased varia- functionally related (see text). POMT: protein