Soleus muscle in glycosylation-deficient muscular dystrophy is protected from contraction-induced injury

Abstract

The glycosylation of dystroglycan is required for its function as a high-affinity laminin receptor, and loss of dystroglycan glycosylation results in congenital muscular dystrophy. The purpose of this study was to investigate the functional defects in slow- and fast-twitch muscles of glycosylation-deficient Large(myd) mice. While a partial alteration in glycosylation of dystroglycan in heterozygous Large(myd/+) mice was not sufficient to alter muscle function, homozygous Large(myd/myd) mice demonstrated a marked reduction in specific force in both soleus and extensor digitorum longus (EDL) muscles. Although EDL muscles from Large(myd/myd) mice were highly susceptible to lengthening contraction-induced injury, Large(myd/myd) soleus muscles surprisingly showed no greater force deficit compared with wild-type soleus muscles even after five lengthening contractions. Despite no increased susceptibility to injury, Large(myd/myd) soleus muscles showed loss of dystroglycan glycosylation and laminin binding activity and dystrophic pathology. Interestingly, we show that soleus muscles have a markedly higher sarcolemma expression of β(1)-containing integrins compared with EDL and gastrocnemius muscles. Therefore, we conclude that β(1)-containing integrins play an important role as matrix receptors in protecting muscles containing slow-twitch fibers from contraction-induced injury in the absence of dystroglycan function, and that contraction-induced injury appears to be a separable phenotype from the dystrophic pathology of muscular dystrophy.

Role of dystroglycan in limiting contraction-induced injury to the sarcomeric cytoskeleton of mature skeletal muscle

“…For example, muscles of knock-in mice carrying a retrotransposon insertion of the gene encoding fukutin maintained only a small level of α-DG hypoglycosylation yet retained 50% of their laminin-binding capacity, whereas mice null for the glycosyltransferase LARGE (Large myd mice), in which glycosylated α-DG was absent, retained less than 5% of laminin-binding capacity (52). Also, the extracellular matrix receptor α7β1 integrin is thought to help preserve the integrity of the basal lamina and limit contractioninduced injury, especially when α-DG function is disrupted (24).…”

“…Defects in the DGC are associated with high susceptibility to severe muscle injury caused by lengthening contractions (21)(22)(23)(24). Muscles of mice deficient for dystrophin (mdx mice) display increased sarcolemmal damage, destabilization of sarcomeres, hypercontraction, and contraction-induced force deficits (22,(25)(26)(27).…”

Laminin-211 in skeletal muscle function

“…74,75 Importantly, a recent report suggests that fiber composition has an impact on protection against contraction-induced injury. 76 Extensor digitorum longus (EDL) and soleus muscle from Large myd mice were subjected to a series of Figure 5. Schematic model of integrin a7b1 and the dystrophin-glycoprotein complex in health and disease.…”

Dystrophin–glycoprotein complex regulates muscle nitric oxide production through mechanoregulation of AMPK signaling

“…The generally accepted role for this complex is to act as a molecular shock absorber and stabilize the plasma membrane during muscle contraction. Disruption of the DGC's linkage between the cytoskeleton and extracellular matrix, such as occurs in DMD (1, 5-7) or with the disruption of α-dystroglycan-laminin binding in glycosylation-deficient muscular dystrophies (8, 9), leads to destabilization of the plasma membrane, rendering skeletal muscle fibers and cardiomyocytes susceptible to stretch-or contraction-induced injury and cell death (10)(11)(12)(13)(14).In addition to this structural role, a signaling function for the DGC has been proposed based on its association with several signaling proteins including Grb2-Sos1 (15), MEK and ERK (16), heterotrimeric G protein subunits (17, 18), archvillin (19), and neuronal nitric oxide synthase (nNOS) (20)(21)(22). The current dogma is that the DGC serves as a passive scaffold for these molecules, anchoring them near sites of action or important partners, with genetic disruption of the DGC leading to mislocalization, destabilization, or ineffective recruitment of these molecules to the complex (23).…”

“…The generally accepted role for this complex is to act as a molecular shock absorber and stabilize the plasma membrane during muscle contraction. Disruption of the DGC's linkage between the cytoskeleton and extracellular matrix, such as occurs in DMD (1,(5)(6)(7) or with the disruption of α-dystroglycan-laminin binding in glycosylation-deficient muscular dystrophies (8,9), leads to destabilization of the plasma membrane, rendering skeletal muscle fibers and cardiomyocytes susceptible to stretch-or contraction-induced injury and cell death (10)(11)(12)(13)(14).…”