scholarly journals Mitochondrial dysfunction in skeletal muscle of fukutin deficient mice is resistant to exercise- and AICAR-induced rescue

2020 ◽  
Author(s):  
W. Michael Southern ◽  
Anna S. Nichenko ◽  
Anita E. Qualls ◽  
Kensey Portman ◽  
Ariel Gidon ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Function ◽  
Ampk Signaling ◽  
Beneficial Effects ◽  
Glycoprotein Complex ◽  
Metabolic Defects ◽  
Dystrophin Glycoprotein Complex ◽  
Mitochondrial Defects ◽  
Primary Basis ◽  
Dystrophin Glycoprotein

AbstractDisruptions in the dystrophin-glycoprotein complex (DGC) are clearly the primary basis underlying various forms of muscular dystrophies and dystroglycanopathies, but the cellular consequences of DGC disruption are still being investigated. Mitochondrial abnormalities are becoming an apparent consequence and contributor to dystrophy disease pathology. Herein, we demonstrate that muscle-specific deletion of the fukutin gene [Myf5/fktn-KO mice (KO)], a model of secondary dystroglycanopathy, results in ~30% lower muscle strength (P<0.001) and 16% lower mitochondrial function (P=0.002) compared to healthy littermate controls (LM). We also observed ~80% lower PGC-1α signaling (P=0.004), a primary transcription factor for mitochondrial biogenesis, in KO mice that likely contributes to the mitochondrial defects. PGC-1α is post-translationally regulated via phosphorylation by AMPK. Treatment with the AMPK agonist AICAR (5-aminoimidazole-4-carboxamide ribonucleotide) failed to rescue mitochondrial deficits in KO mice (P=0.458) but did have beneficial (~30% greater) effects on recovery of muscle contractility following injury in both LM and KO mice compared to saline treatment (P=0.006). The beneficial effects of AMPK stimulation via AICAR on muscle function may be partially explained by AMPK’s other role of regulating skeletal muscle autophagy, a cellular process critical for clearance of damaged and/or dysfunctional organelles. Two primary conclusions can be drawn from this data, 1) fukutin deletion produces intrinsic muscular metabolic defects that likely contribute to dystroglycanopathy disease pathology, and 2) AICAR treatment accelerates recovery of muscle function following injury suggesting AMPK signaling as a possible target for therapeutic strategies.

scholarly journals Impact of sarcoglycan complex on mechanical signal transduction in murine skeletal muscle

2006 ◽  
Vol 290 (2) ◽  
pp. C411-C419 ◽  
Author(s):  
Elisabeth R. Barton
Keyword(s):  
Skeletal Muscle ◽  
Mechanical Load ◽  
Eccentric Contraction ◽  
Eccentric Contractions ◽  
Normal Muscle ◽  
Glycoprotein Complex ◽  
Dystrophin Glycoprotein Complex ◽  
Severe Pathology ◽  
Murine Skeletal Muscle ◽  
Dystrophin Glycoprotein

Loss of the dystrophin glycoprotein complex (DGC) or a subset of its components can lead to muscular dystrophy. However, the patterns of symptoms differ depending on which proteins are affected. Absence of dystrophin leads to loss of the entire DGC and is associated with susceptibility to contractile injury. In contrast, muscles lacking γ-sarcoglycan (γ-SG) display little mechanical fragility and still develop severe pathology. Animals lacking dystrophin or γ-SG were used to identify DGC components critical for sensing dynamic mechanical load. Extensor digitorum longus muscles from 7-wk-old normal (C57), dystrophin- null ( mdx), and γ-SG-null ( gsg−/−) mice were subjected to a series of eccentric contractions, after which ERK1/2 phosphorylation levels were determined. At rest, both dystrophic strains had significantly higher ERK1 phosphorylation, and gsg−/− muscle also had heightened ERK2 phosphorylation compared with wild-type controls. Eccentric contractions produced a significant and transient increase in ERK1/2 phosphorylation in normal muscle, whereas the mdx strain displayed no significant proportional change of ERK1/2 phosphorylation after eccentric contraction. Muscles from gsg−/− mice had no significant increase in ERK1 phosphorylation; however, ERK2 phosphorylation was more robust than in C57 controls. The reduction in mechanically induced ERK1 phosphorylation in gsg−/− muscle was not dependent on age or severity of phenotype, because muscle from both young and old (age 20 wk) animals exhibited a reduced response. Immunoprecipitation experiments revealed that γ-SG was phosphorylated in normal muscle after eccentric contractions, indicating that members of the DGC are modified in response to mechanical perturbation. This study provides evidence that the SGs are involved in the transduction of mechanical information in skeletal muscle, potentially unique from the entire DGC.

scholarly journals Sarcospan-Deficient Mice Maintain Normal Muscle Function

2000 ◽  
Vol 20 (5) ◽  
pp. 1669-1677 ◽  
Author(s):  
Connie S. Lebakken ◽  
David P. Venzke ◽  
Ronald F. Hrstka ◽  
Christina M. Consolino ◽  
John A. Faulkner ◽  
...  
Keyword(s):  
Muscle Function ◽  
Normal Force ◽  
Membrane Component ◽  
Normal Muscle ◽  
Glycoprotein Complex ◽  
Dystrophin Glycoprotein Complex ◽  
Evans Blue Uptake ◽  
Dystrophin Glycoprotein ◽  
Deficient Mice ◽  
Sarcolemmal Integrity

ABSTRACT Sarcospan is an integral membrane component of the dystrophin-glycoprotein complex (DGC) found at the sarcolemma of striated and smooth muscle. The DGC plays important roles in muscle function and viability as evidenced by defects in components of the DGC, which cause muscular dystrophy. Sarcospan is unique among the components of the complex in that it contains four transmembrane domains with intracellular N- and C-terminal domains and is a member of the tetraspan superfamily of proteins. Sarcospan is tightly linked to the sarcoglycans, and together these proteins form a subcomplex within the DGC. Stable expression of sarcospan at the sarcolemma is dependent upon expression of the sarcoglycans. Here we describe the generation and analysis of mice carrying a null mutation in the Sspngene. Surprisingly, the Sspn-deficient muscle maintains expression of other components of the DGC at the sarcolemma, and no gross histological abnormalities of muscle from the mice are observed. The Sspn-deficient muscle maintains sarcolemmal integrity as determined by serum creatine kinase and Evans blue uptake assays, and the Sspn-deficient muscle maintains normal force and power generation capabilities. These data suggest either that sarcospan is not required for normal DGC function or that theSspn-deficient muscle is compensating for the absence of sarcospan, perhaps by utilizing another protein to carry out its function.

Pharmacological rescue of the dystrophin-glycoprotein complex in Duchenne and Becker skeletal muscle explants by proteasome inhibitor treatment

2006 ◽  
Vol 290 (2) ◽  
pp. C577-C582 ◽  
Author(s):  
Stefania Assereto ◽  
Silvia Stringara ◽  
Federica Sotgia ◽  
Gloria Bonuccelli ◽  
Aldobrando Broccolini ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscular Dystrophy ◽  
Proteasome Inhibitor ◽  
Becker Muscular Dystrophy ◽  
Culture Conditions ◽  
Mdx Mouse ◽  
Glycoprotein Complex ◽  
Dystrophin Glycoprotein Complex ◽  
Novel Method ◽  
Dystrophin Glycoprotein

In this report, we have developed a novel method to identify compounds that rescue the dystrophin-glycoprotein complex (DGC) in patients with Duchenne or Becker muscular dystrophy. Briefly, freshly isolated skeletal muscle biopsies (termed skeletal muscle explants) from patients with Duchenne or Becker muscular dystrophy were maintained under defined cell culture conditions for a 24-h period in the absence or presence of a specific candidate compound. Using this approach, we have demonstrated that treatment with a well-characterized proteasome inhibitor, MG-132, is sufficient to rescue the expression of dystrophin, β-dystroglycan, and α-sarcoglycan in skeletal muscle explants from patients with Duchenne or Becker muscular dystrophy. These data are consistent with our previous findings regarding systemic treatment with MG-132 in a dystrophin-deficient mdx mouse model (Bonuccelli G, Sotgia F, Schubert W, Park D, Frank PG, Woodman SE, Insabato L, Cammer M, Minetti C, and Lisanti MP. Am J Pathol 163: 1663–1675, 2003). Our present results may have important new implications for the possible pharmacological treatment of Duchenne or Becker muscular dystrophy in humans.

scholarly journals Increasing α7β1-integrin promotes muscle cell proliferation, adhesion, and resistance to apoptosis without changing gene expression

2008 ◽  
Vol 294 (2) ◽  
pp. C627-C640 ◽  
Author(s):  
Jianming Liu ◽  
Dean J. Burkin ◽  
Stephen J. Kaufman
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Extracellular Matrix ◽  
Muscular Dystrophy ◽  
Expression Profiles ◽  
C2c12 Cells ◽  
Glycoprotein Complex ◽  
Dystrophin Glycoprotein Complex ◽  
Dystrophin Glycoprotein

The dystrophin-glycoprotein complex maintains the integrity of skeletal muscle by associating laminin in the extracellular matrix with the actin cytoskeleton. Several human muscular dystrophies arise from defects in the components of this complex. The α7β1-integrin also binds laminin and links the extracellular matrix with the cytoskeleton. Enhancement of α7-integrin levels alleviates pathology in mdx/utrn−/− mice, a model of Duchenne muscular dystrophy, and thus the integrin may functionally compensate for the absence of dystrophin. To test whether increasing α7-integrin levels affects transcription and cellular functions, we generated α7-integrin-inducible C2C12 cells and transgenic mice that overexpress the integrin in skeletal muscle. C2C12 myoblasts with elevated levels of integrin exhibited increased adhesion to laminin, faster proliferation when serum was limited, resistance to staurosporine-induced apoptosis, and normal differentiation. Transgenic expression of eightfold more integrin in skeletal muscle did not result in notable toxic effects in vivo. Moreover, high levels of α7-integrin in both myoblasts and in skeletal muscle did not disrupt global gene expression profiles. Thus increasing integrin levels can compensate for defects in the extracellular matrix and cytoskeleton linkage caused by compromises in the dystrophin-glycoprotein complex without triggering apparent overt negative side effects. These results support the use of integrin enhancement as a therapy for muscular dystrophy.

scholarly journals Dystrophin insufficiency causes selective muscle histopathology and loss of dystrophin‐glycoprotein complex assembly in pig skeletal muscle

2013 ◽  
Vol 28 (4) ◽  
pp. 1600-1609 ◽  
Author(s):  
Katrin Hollinger ◽  
Cai X. Yang ◽  
Robyn E. Montz ◽  
Dan Nonneman ◽  
Jason W. Ross ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Complex Assembly ◽  
Glycoprotein Complex ◽  
Dystrophin Glycoprotein Complex ◽  
Dystrophin Glycoprotein
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