Histol Histopathol (1998) 13: 283-291 Histology and 001: 10.14670/HH-13.283 Histopathology http://www.hh.um.es From Cell Biology to Tissue Engineering Invited Review The cytoskeleton in skeletal, cardiac and smooth muscle cells M.H. Stromer Department of Animal Science, Iowa State University, Ames, lA, USA Summary. The muscle cell cytoskeleton consists of cell that maintain the overall structural order of proteins or structures whose primary function is to link, components inside the muscle cell but that do not anchor or tether structural components inside the cell. actually participate in contraction per se. Unfortunately Two important attributes of the cytoskeleton are strength this has sometimes evoked the concept that the of the various attachments and flexibility to accommo­ cytoskeleton of muscle cells is relatively static and less date the changes in cell geometry that occur during interesting than the contractile machinery. The well­ contraction. In striated muscle cells, extramyofibrillar documented observations that skeletal muscle maintains and intramyofibrillar domains of the cytoskeleton have a remarkably constant cell volume during contraction by been identified, Evidence of the extramyofibrillar simultaneously increasing cell diameter as cell length cytoskeleton is seen at the cytoplasmic face of the decreases and that smooth muscle cells can contract to sarcolemma in striated muscle where vinculin- and 60% of rest length and can return to rest length with dystrophin-rich costameres adjacent to sarcomeric Z their internal structure relatively intact suggest that the lines anchor intermediate filaments that span from cytoskeleton must be highly adaptable to cell shape peripheral myofibrils to the sarcolemma. Intermediate changes. How this adaptation occurs is generally filaments also link Z lines of adjacent myofibrils and unknown. For this review, a muscle cell cytoskeletal may, in some muscles, link successive Z lines within a component is defined as a protein or structure whose myofibril at the surface of the myofibril. The intramyo­ primary role is usually considered to be that of a linker, fibrillar cytoskeletal domain includes elastic titin a n anchor or tether that connects two structural filaments from adjacent sarcomeres that are anchored in components. In striated muscle, two compartments of the Z line and continue through the M line at the center the cytoskeleton will be discussed, the extramyofibrillar of the sarcomere; inelastic nebulin filaments also and the intramyofibrillar. The principal proteins that anchored in the Z line and co-extensible with thin constitute the thick and the thin sarcomeric filaments filaments; the Z line, which also anchors thin filaments will not be considered as part of the muscle cell from adjacent sarcomeres; and the M line, which forms cytoskeleton. This definition is consistent with that bridges between the centers of adjacent thick filaments, proposed by Walsh (1997). For reviews on the muscle In smooth muscle, the cytoskeleton includes adherens cell cytoskeleton, see Small et al. (1992) and Stromer junctions at the cytoplasmic face of the sarcolemma, (1995). The existence in muscle of multiple isoforms of which a nchor B-actin filaments and intermediate actin, however, complicate the classification system. filaments of the cytoskeleton, and dense bodies in the Early embryonic and some cultured skeletal muscle cells cytoplasm, which also anchor actin filaments and express mainly cardiac a-sarcomeric actin and intermediate filaments and which may be the interface cytoplasmic or nonmuscle 13- and y-actin isoforms between cytoskeletal and contractile elements. (Vandekerckhove et aI., 1986; Otey et aI., 1988). In adult skeletal muscle, the skeletal a-sarcomeric isoform Key words: Cytoskeleton, Muscle, Skeletal, Cardiac, predominates but the cytoplasmic 13- and y-isoforms are Smooth also present and apparently are not completely segregated from the a-isoform. Otey et al. (1988) used immunofluorescence to demonstrate that isolated Introduction myofibrils from mature skeletal muscle contained mainly a-actin but also contained lesser amounts of y­ The muscle cell cytoskeleton has frequently been cytoplasmic actin, Immunogold labeling of L6 cells considered to include those components of the muscle showed that y-cytoplasmic actin predominated in cortical actin filaments, skeletal a-actin predominated in nascent Offprint requests to: Dr. Marvin H. Stromer, 3116 Molecular Biology myofibrils and both actin isoforms existed at each of Building, Iowa State University, Ames, IA 50011 -3260, USA these locations (Otey et aI., 1988). Smooth muscle cells 284 The muscle cell cytoskeleton in th e adult ve rtebrate vascul ar and di gestive systems th e sarcolemm a by f3-d ys troglyca n, a 43 kDa trans­ contain up to 30% of the total ac tin in th e 13 - and y­ membrane subunit of dystroglycan, a glyco pro tein th at cy topl asmi c isoform s and th e remain der in a - and y­ also contain s a -d ys troglycan, a 156 kD a extracellul ar contrac til e isoform s (Small , 1995). A furthe r laminin-binding subunit (Henry and Camp be ll , 1996). complicating factor is that there is a possibility th at some The biological fun cti ons of the dystroglyca n compl ex in protein s such as titin, nebulin ~ n d myosin binding stri ated muscl e and in other ti ss ues have been rev iewed protein C (MyBP-C), usuall y considered as cy toskeletal by Matsumura et al. ( 1997). The amino-terminal domain pro teins, may modul ate th e acti on of contrac til e protein s of dys trophin contains an ac tin binding domain and is in thi c k and in thin fil ame nt s. A n example is th e th ought to link y-actin fil ament s to th e sarcolemm a. inhibition of in vitro motility of F-actin or reconstituted Although the first three domains of dystrophin ex hi bit thin fil aments when titin was bound to th ese fil ament s sequence homology with actin cross-linking proteins (Kell erm ayer and Granzier, 1996). These exampl es point such as a -actinin and spec trin , Rybakova et al. (1996) out both the complex ity of the muscle ce ll cy toskeleton found that a dystrophin-glycoprotein complex could not and why thi s is an exciting area of research. cross-link F-actin fil ament s. Instea d, Rybakova et al. (1996) identified an additional actin binding sit e near th e Striated muscle ce nter of th e dystrophin rod domain and observed th at when the dystro phin-glycoprotein compl ex was bound to The extramyofibrillar cytoskeleton: Connections between F- actin, th e depolymeri zati on of F- ac tin was slowed. the sarcolemma and peripheral myofibrils These observa tions suggest th at dystrophin may interact with up to 24 actin monomers and may bind along th e The locali za ti on, by immunoflu o rescence, o f side of actin fil aments instead of, or in addition to, the vin culin, a 116 kDa protein , in rib-like bands call ed end . In ra t cardi ac myocytes, dys trophin is not prese nt in costameres th at are located opposit e Z lines at th e a costameri c pattern , but in stead is uni fo rml y distributed cy topl asmi c face of the sarcolemm a in ca rdiac mu scl e at the cytopl asmic fa ce of non-interca lated di sk regions (Pardo et aI. , 1983a) and in skeletal muscl e (Pardo et aI. , of the sarcolemma (Stevenso n et aI. , 1997). Su bce llular 1983b) and at intercalated di sks of ca rdiac mu scle fractionati on of rabbit ventricles demonstra ted th at about (Pardo et aI. , 1983a) suggested th at fil ament attachm ent 55 % of dystrophin was recovered with the sa rcolemm a sit es ex isted at th e sarcole mma. This provided an and 35 % of dystrophin was associa te d with the ex pl anati on for how the fil aments obse rved by Pi erobon­ myo fibrill ar fracti on (Meng et aI. , 1996). Immu nogold Bormi oli ( 198 1) in th e s pace betwee n Z lines of labeling of th ese myofibrils showed that Z lin es were peripheral myofibrils and th e sarcolemm a of skeletal preferentiall y labeled. Additional expe riments will be mu scl e could be anchored at th e membrane. Myo­ needed to dete rmine th e s ig ni f icance o f th e two tendinous and neuromuscular junctions in av ian anteri or subsa rcolemm al distributio ns of dystrophin in skeletal lati ssimus dorsi (ALD) and posteri or lati ss imus dorsi and ca rdiac mu scle and of the presence of dystrophin at (PLD) twitch fibers, and subsa rcoJemm al de nse patches the Z line. over th e I bands in tonic ALD fi be rs, all contain vinculin The inte rcala ted di sk in ca rdi ac mu scle is a (S hea r and Bl ock, 1985). The colocali zati on of y-actin, speciali zed cell-cell cont act th at consists of three intermedi ate filament pro teins and spectrin with vinculin morphologica ll y identifiable regions. The nex us or ga p at costa me res (Craig a nd Pardo, 1983) prov id ed juncti on is para ll el to th e myofib ril ax is, th e mac ul a additional ev id ence that costameres are sit es where adh erens or desmosome is import ant for ce ll-ce ll cytoskeletal fil aments are attached to the sarcolemm a. adh esion and also serv es as an anchor for desmi n­ Both Pierobon-Bormioli (198 1) and Pardo et al.