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Muscle Degeneration Without Mechanical Injury in Sarcoglycan Deficiency

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Muscle Degeneration Without Mechanical Injury in Sarcoglycan Deficiency Proc. Natl. Acad. Sci. USA Vol. 96, pp. 10723–10728, September 1999 Cell Biology Muscle degeneration without mechanical injury in sarcoglycan deficiency A. A. HACK*†,L.CORDIER‡,D.I.SHOTURMA‡,M.Y.LAM†,H.L.SWEENEY‡, AND E. M. MCNALLY†§ *Department of Molecular Genetics and Cell Biology and †Department of Medicine, Section of Cardiology, University of Chicago, 5841 South Maryland Avenue, Chicago, IL 60637; and ‡Department of Physiology, A700 Richards Building, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6085 Edited by Louis M. Kunkel, Harvard Medical School, Boston, MA, and approved July 21, 1999 (received for review April 29, 1999) ABSTRACT In humans, mutations in the genes encoding growth factor-like motif and is suggestive of a cell surface components of the dystrophin–glycoprotein complex cause receptor (30); its exact role is unknown. muscular dystrophy. Specifically, primary mutations in the Dystrophin binds actin at its amino terminus and along its genes encoding ␣-, ␤-, ␥-, and ␦-sarcoglycan have been rod domain (31–33). In the cytoplasm, the carboxyl terminus identified in humans with limb-girdle muscular dystrophy. of dystrophin interacts with dystroglycan, a transmembrane Mice lacking ␥-sarcoglycan develop progressive muscular protein that associates with the extracellular matrix (ECM) dystrophy similar to human muscular dystrophy. Without protein laminin (12, 34). In skeletal muscle myotubes, this link ␥-sarcoglycan, ␤- and ␦-sarcoglycan are unstable at the is thought to be critical for mechanical integrity and resistance muscle membrane and ␣-sarcoglycan is severely reduced. The to hypoosmotic shock (35–37). The absence of dystrophin may expression and localization of dystrophin, dystroglycan, and lead to disruptions of the muscle plasma membrane during laminin-␣2, a mechanical link between the actin cytoskeleton repeated cycles of contraction and relaxation, resulting in and the extracellular matrix, appears unaffected by the loss of muscle degeneration and muscular dystrophy (38, 39). Eleva- sarcoglycan. We assessed the functional integrity of this tions in intramyocyte calcium levels coupled with the appear- mechanical link and found that isolated muscles lacking ance of muscle enzymes in the serum of DMD patients and ␥-sarcoglycan showed normal resistance to mechanical strain mdx mice are consistent with such a defect in the sarcolemma induced by eccentric muscle contraction. Sarcoglycan- (38, 40–42). However, other mechanisms may be responsible deficient muscles also showed normal peak isometric and for both muscle enzyme release and calcium entry into the tetanic force generation. Furthermore, there was no evidence dystrophic myofiber. Moreover, eccentric contractions cause a for contraction-induced injury in mice lacking ␥-sarcoglycan significant increase in mechanically induced sarcolemmal that were subjected to an extended, rigorous exercise regimen. damage in isolated mdx muscles (43–45). In mdx muscle there These data demonstrate that mechanical weakness and con- is also a significant linear relationship between peak force and traction-induced muscle injury are not required for muscle the proportion of damaged fibers, suggesting that a mechanical degeneration and the dystrophic process. Thus, a nonme- defect results from the absence of dystrophin and arguing that chanical mechanism, perhaps involving some unknown sig- this mechanical defect causes muscular dystrophy (45). ␥ naling function, likely is responsible for muscular dystrophy -Sarcoglycan is a 35-kDa dystrophin-associated protein, ␥ where sarcoglycan is deficient. and mutations in -sarcoglycan are associated with the human disease SCARMD (severe childhood autosomal recessive mus- The dystrophin–glycoprotein complex (DGC) is a multimeric cular dystrophy), also known as limb-girdle muscular dystrophy type 2C (LGMD-2C). Mice lacking ␥-sarcoglycan were gen- assembly of both transmembrane- and membrane-associated erated by using homologous recombination in embryonic stem proteins found in both skeletal and cardiac muscle (1–4). cells by targeting exon 2 of the murine ␥-sarcoglycan gene to Molecular and biochemical analyses have demonstrated that create a null allele. Like LGMD patients, mice lacking ␥-sar- the DGC is composed of the following components: dystro- Ϫ͞Ϫ coglycan (gsg ) showed pronounced skeletal and cardiac phin, an elongated cytoskeletal protein that binds actin (5–7); muscle degeneration with reduced survival. In addition to the sarcoglycan, a multisubunit transmembrane glycoprotein (8– Ϫ͞Ϫ loss of ␥-sarcoglycan, muscle from gsg animals showed 10); dystroglycan, a laminin receptor that also binds dystrophin reduced levels of ␤- and ␦-sarcoglycan but exhibited normal (11, 12); the syntrophins, mammalian homologues of the staining patterns for dystrophin, dystroglycan, and laminin-␣2. Torpedo 58-kDa postsynaptic protein (13–15); and dystrobre- Thus, sarcoglycan loss was sufficient to induce muscular vin, a dystrophin-related, dystrophin-associated protein (16– dystrophy in the presence of an apparently intact dystrophin– 21). Mutations in the dystrophin gene result in Duchenne͞ dystroglycan–laminin axis. Becker muscular dystrophy (DMD͞BMD), a common X- To determine whether mechanical fragility was a conse- linked disorder (5, 6). The mdx mouse is a spontaneously quence of the loss of an intact sarcoglycan complex, we arising mutant that lacks full-length dystrophin and serves as performed mechanical measurements on isolated muscles a model for DMD (22). from gsgϪ͞Ϫ animals and found normal muscle mechanics. To In muscle, there are at least four sarcoglycan subunits, ␣, ␤, ␥ ␦ confirm the physiologic significance of our findings, we stren- , and , and mutations in any of these four can result in uously exercised gsgϪ͞Ϫ animals for a prolonged period and autosomal recessive muscular dystrophy (23–27). A more found no evidence for contraction-induced injury or acceler- widely distributed fifth sarcoglycan, ␧-sarcoglycan, recently has been identified (28, 29), suggesting that sarcoglycan complexes This paper was submitted directly (Track II) to the Proceedings office. may also function in tissues other than muscle. Sarcoglycan has Abbreviations: DGC, dystrophin–glycoprotein complex; DMD͞BMD, a primary structure that includes an extracellular epidermal Duchenne͞Becker muscular dystrophy; LGMD, limb-girdle muscular dystrophy; ECC, eccentric contraction; EDL, extensor digitorum The publication costs of this article were defrayed in part by page charge longus. §To whom reprint requests should be addressed at: Department of payment. This article must therefore be hereby marked ‘‘advertisement’’ in Medicine, Section of Cardiology, The University of Chicago, 5841 accordance with 18 U.S.C. §1734 solely to indicate this fact. South Maryland Avenue, MC 6088, Chicago, IL 60637. E-mail: PNAS is available online at www.pnas.org. [email protected]. 10723 Downloaded by guest on September 24, 2021 10724 Cell Biology: Hack et al. Proc. Natl. Acad. Sci. USA 96 (1999) ated disease progression. These data are consistent with a minimum of 4 hr. Length of swim was increased daily by 5 min nonmechanical defect producing myofiber degeneration and per session until a final duration of two 1-hr sessions per day muscular dystrophy. Because sarcoglycan loss is also a feature was achieved. The length of the conditioning period was 10 of DMD, this same nonmechanical defect may be contributing days. Animals were exercised 6 days per week, and the protocol to pathology in dystrophin-deficient muscular dystrophy. Fur- was continued for 7 weeks including the 10-day conditioning thermore, these data reveal that the DGC is a multifunctional period. One homozygous mutant (gsgϪ͞Ϫ) mouse was removed complex and define an independent role for ␥-sarcoglycan in from the protocol after week 3 as a result of a cutaneous muscle survival. infection that failed to heal after treatment with oral antibi- otics. Animals were observed for 15 min before and after MATERIALS AND METHODS swimming for behavior and activity level. Animals were weighed at the end of each week. Blood was collected on the Animals. All mice were housed and treated in accordance second day after the swimming protocol was completed, and with standards set by the University of Chicago Institutional serum creatine kinase levels were measured as described Animal Care and Use Committee and the University of above. Pennsylvania Animal Care and Use Committee. Genotypes Histology. Animals were sacrificed 2 days after the comple- were determined by PCR as described previously (46). Age- tion of the 7-week swimming protocol. Femoral quadriceps, matched wild-type 129SvJ animals were used as controls (The triceps bracheii, gastrocnemius, and heart were dissected from Jackson Laboratory). Animals used for study were anesthe- surrounding tissues, frozen in liquid nitrogen-cooled isopen- tized and killed by cervical dislocation. Serum creatine kinase tane, and stored at Ϫ80°C for further analysis. Frozen sections levels were determined from tail vein sampling collected in a from each tissue were cut at midlength at Ϫ20°C by using a Microtainer Serum Separator tube (Becton Dickinson) and cryostat (Leica), and histology was performed as described analyzed by using a Vitros DT60II discrete chemistry analyzer previously (46). A scale from 0 to 3 was used to score the (Ortho Clinical Products, Raritan, NJ). percentage of the section displaying fibrosis, adipose tissue Muscle Preparation and
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