scholarly journals Role of dystrophin and utrophin for assembly and function of the dystrophin glycoprotein complex in non-muscle tissue

2006 ◽  
Vol 63 (14) ◽  
pp. 1614-1631 ◽  
Author(s):  
T. Haenggi ◽  
J. -M. Fritschy
Keyword(s):  
Muscle Tissue ◽  
Glycoprotein Complex ◽  
Dystrophin Glycoprotein Complex ◽  
And Function ◽  
Dystrophin Glycoprotein

scholarly journals Contraction-Induced Loss of Plasmalemmal Electrophysiological Function Is Dependent on the Dystrophin Glycoprotein Complex

2021 ◽  
Vol 12 ◽  
Author(s):  
Cory W. Baumann ◽  
Angus Lindsay ◽  
Sylvia R. Sidky ◽  
James M. Ervasti ◽  
Gordon L. Warren ◽  
...  
Keyword(s):  
M Wave ◽  
Glycoprotein Complex ◽  
Dystrophic Mouse ◽  
Dystrophin Deficiency ◽  
Torque Loss ◽  
Dystrophin Glycoprotein Complex ◽  
The Many ◽  
Dystrophin Glycoprotein ◽  
Mouse Lines

Weakness and atrophy are key features of Duchenne muscular dystrophy (DMD). Dystrophin is one of the many proteins within the dystrophin glycoprotein complex (DGC) that maintains plasmalemmal integrity and cellular homeostasis. The dystrophin-deficient mdx mouse is also predisposed to weakness, particularly when subjected to eccentric (ECC) contractions due to electrophysiological dysfunction of the plasmalemma. Here, we determined if maintenance of plasmalemmal excitability during and after a bout of ECC contractions is dependent on intact and functional DGCs rather than, solely, dystrophin expression. Wild-type (WT) and dystrophic mice (mdx, mL172H and Sgcb−/− mimicking Duchenne, Becker and Limb-girdle Type 2E muscular dystrophies, respectively) with varying levels of dystrophin and DGC functionality performed 50 maximal ECC contractions with simultaneous torque and electromyographic measurements (M-wave root-mean-square, M-wave RMS). ECC contractions caused all mouse lines to lose torque (p<0.001); however, deficits were greater in dystrophic mouse lines compared to WT mice (p<0.001). Loss of ECC torque did not correspond to a reduction in M-wave RMS in WT mice (p=0.080), while deficits in M-wave RMS exceeded 50% in all dystrophic mouse lines (p≤0.007). Moreover, reductions in ECC torque and M-wave RMS were greater in mdx mice compared to mL172H mice (p≤0.042). No differences were observed between mdx and Sgcb−/− mice (p≥0.337). Regression analysis revealed ≥98% of the variance in ECC torque loss could be explained by the variance in M-wave RMS in dystrophic mouse lines (p<0.001) but not within WT mice (R2=0.211; p=0.155). By comparing mouse lines that had varying amounts and functionality of dystrophin and other DGC proteins, we observed that (1) when all DGCs are intact, plasmalemmal action potential generation and conduction is maintained, (2) deficiency of the DGC protein β-sarcoglycan is as disruptive to plasmalemmal excitability as is dystrophin deficiency and, (3) some functionally intact DGCs are better than none. Our results highlight the significant role of the DGC plays in maintaining plasmalemmal excitability and that a collective synergism (via each DGC protein) is required for this complex to function properly during ECC contractions.

Fast-twitch skeletal muscles of dystrophic mouse pups are resistant to injury from acute mechanical stress

2002 ◽  
Vol 283 (4) ◽  
pp. C1090-C1101 ◽  
Author(s):  
Robert W. Grange ◽  
Thomas G. Gainer ◽  
Krista M. Marschner ◽  
Robert J. Talmadge ◽  
James T. Stull
Keyword(s):  
Skeletal Muscles ◽  
Mechanical Injury ◽  
Membrane Injury ◽  
Glycoprotein Complex ◽  
Dystrophin Glycoprotein Complex ◽  
Duchenne's Muscular Dystrophy ◽  
Fast Twitch ◽  
Dystrophin Glycoprotein

Loss of the dystrophin-glycoprotein complex from muscle sarcolemma in Duchenne's muscular dystrophy (DMD) renders the membrane susceptible to mechanical injury, leaky to Ca2+, and disrupts signaling, but the precise mechanism(s) leading to the onset of DMD remain unclear. To assess the role of mechanical injury in the onset of DMD, extensor digitorum longus (EDL) muscles from C57 (control), mdx, and mdx-utrophin-deficient [ mdx:utrn(−/−); dystrophic] pups aged 9–12 days were subjected to an acute stretch-injury or no-stretch protocol in vitro. Before the stretches, isometric stress was attenuated for mdx:utrn(−/−) compared with control muscles at all stimulation frequencies ( P< 0.05). During the stretches, EDL muscles for each genotype demonstrated similar mean stiffness values. After the stretches, isometric stress during a tetanus was decreased significantly for both mdx and mdx:utrn(−/−) muscles compared with control muscles ( P < 0.05). Membrane injury assessed by uptake of procion orange dye was greater for dystrophic compared with control EDL ( P < 0.05), but, within each genotype, the percentage of total cells taking up dye was not different for the no-stretch vs. stretch condition. These data suggest that the sarcolemma of maturing dystrophic EDL muscles are resistant to acute mechanical injury.

scholarly journals Caveolin 3, Flotillin 1 and Influenza Virus Hemagglutinin Reside in Distinct Domains on the Sarcolemma of Skeletal Myofibers

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Mika Kaakinen ◽  
Tuula Kaisto ◽  
Paavo Rahkila ◽  
Kalervo Metsikkö
Keyword(s):  
Distribution Patterns ◽  
Cholesterol Depletion ◽  
Similar Distribution ◽  
Glycoprotein Complex ◽  
Influenza Hemagglutinin ◽  
Influenza Virus Hemagglutinin ◽  
Dystrophin Glycoprotein Complex ◽  
Dystrophin Glycoprotein ◽  
Similar Distribution Pattern

We examined the distribution of selected raft proteins on the sarcolemma of skeletal myofibers and the role of cholesterol environment in the distribution. Immunofluorescence staining showed that flotillin-1 and influenza hemagglutinin exhibited rafts that located in the domains deficient of the dystrophin glycoprotein complex, but the distribution patterns of the two proteins were different. Cholesterol depletion from the sarcolemma by means of methyl-β-cyclodextrin resulted in distorted caveolar morphology and redistribution of the caveolin 3 protein. Concomitantly, the water permeability of the sarcolemma increased significantly. However, cholesterol depletion did not reshuffle flotillin 1 or hemagglutinin. Furthermore, a hemagglutinin variant that lacked a raft-targeting signals exhibited a similar distribution pattern as the native raft protein. These findings indicate that each raft protein exhibits a strictly defined distribution in the sarcolemma. Only the distribution of caveolin 3 that binds cholesterol was exclusively dependent on cholesterol environment.

scholarly journals Membrane Targeting and Stabilization of Sarcospan Is Mediated by the Sarcoglycan Subcomplex

1999 ◽  
Vol 145 (1) ◽  
pp. 153-165 ◽  
Author(s):  
Rachelle H. Crosbie ◽  
Connie S. Lebakken ◽  
Kathleen H. Holt ◽  
David P. Venzke ◽  
Volker Straub ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Muscular Dystrophy ◽  
Genetic Mutations ◽  
Myotendinous Junction ◽  
Normal Muscle ◽  
Glycoprotein Complex ◽  
Muscle Plasma Membrane ◽  
Dystrophin Glycoprotein Complex ◽  
And Function ◽  
Dystrophin Glycoprotein

The dystrophin–glycoprotein complex (DGC) is a multisubunit complex that spans the muscle plasma membrane and forms a link between the F-actin cytoskeleton and the extracellular matrix. The proteins of the DGC are structurally organized into distinct subcomplexes, and genetic mutations in many individual components are manifested as muscular dystrophy. We recently identified a unique tetraspan-like dystrophin-associated protein, which we have named sarcospan (SPN) for its multiple sarcolemma spanning domains (Crosbie, R.H., J. Heighway, D.P. Venzke, J.C. Lee, and K.P. Campbell. 1997. J. Biol. Chem. 272:31221–31224). To probe molecular associations of SPN within the DGC, we investigated SPN expression in normal muscle as a baseline for comparison to SPN's expression in animal models of muscular dystrophy. We show that, in addition to its sarcolemma localization, SPN is enriched at the myotendinous junction (MTJ) and neuromuscular junction (NMJ), where it is a component of both the dystrophin– and utrophin–glycoprotein complexes. We demonstrate that SPN is preferentially associated with the sarcoglycan (SG) subcomplex, and this interaction is critical for stable localization of SPN to the sarcolemma, NMJ, and MTJ. Our experiments indicate that assembly of the SG subcomplex is a prerequisite for targeting SPN to the sarcolemma. In addition, the SG– SPN subcomplex functions to stabilize α-dystroglycan to the muscle plasma membrane. Taken together, our data provide important information about assembly and function of the SG–SPN subcomplex.

Differential requirement for individual sarcoglycans and dystrophin in the assembly and function of the dystrophin-glycoprotein complex

2000 ◽  
Vol 113 (14) ◽  
pp. 2535-2544 ◽  
Author(s):  
A.A. Hack ◽  
M.Y. Lam ◽  
L. Cordier ◽  
D.I. Shoturma ◽  
C.T. Ly ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Muscular Dystrophy ◽  
Eccentric Contraction ◽  
Muscle Membrane ◽  
Glycoprotein Complex ◽  
Dystrophin Glycoprotein Complex ◽  
Alpha Beta ◽  
And Function ◽  
Dystrophin Glycoprotein

Sarcoglycan is a multimeric, integral membrane glycoprotein complex that associates with dystrophin. Mutations in individual sarcoglycan subunits have been identified in inherited forms of muscular dystrophy. To evaluate the contributions of sarcoglycan and dystrophin to muscle membrane stability and muscular dystrophy, we compared muscle lacking specific sarcoglycans or dystrophin. Here we report that mice lacking (delta)-sarcoglycan developed muscular dystrophy and cardiomyopathy similar to mice lacking (gamma)-sarcoglycan. However, unlike muscle lacking (gamma)-sarcoglycan, (delta)-sarcoglycan-deficient muscle was sensitive to eccentric contraction-induced disruption of the plasma membrane. In the absence of (delta)-sarcoglycan, (alpha)-, (beta)- and (gamma)-sarcoglycan were undetectable, while dystrophin was expressed at normal levels. In contrast, without (gamma)-sarcoglycan, reduced levels of (alpha)-, (beta)- and (delta)-sarcoglycan were expressed, glycosylated and formed a complex with each other. Thus, the elimination of (gamma)- and (delta)-sarcoglycan had different molecular consequences for the assembly and function of the dystrophin-glycoprotein complex. Furthermore, these molecular differences were associated with different mechanical consequences for the muscle plasma membrane. Through this in vivo analysis, a model for sarcoglycan assembly is proposed.

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