Muscle inflammation and MHC class I up-regulation in muscular dystrophy with lack of dysferlin: an immunopathological study.
ABSTRACT Muscle inflammation is characteristic of inflammatory myopathies but also occurs in muscular dystrophy with lack of the sarcolemmal protein dysferlin. We quantified inflammatory cells and major histocompatibility complex (MHC) expression in muscle from 10 patients with dysferlinopathy. Infiltrating cells were always present although numbers varied considerably; macrophages were more common than T cells, T cytotoxicity was absent, and MHC class I was overexpressed on muscle fibers. These findings differ from polymyositis (PM) but are closely similar to those in SJL/J mice (which lack dysferlin) and emphasize the relationship between absence of dysferlin and immune system abnormalities in muscle.
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ABSTRACT: A deficiency of the dysferlin protein results in limb girdle muscular dystrophy type 2B and Miyoshi myopathy, with resulting plasma membrane abnormalities in myofibers. Many patients show muscle inflammation, but the molecular mechanisms that initiate and perpetuate this inflammation are not well understood. We previously showed abnormal activation of macrophages and hypothesized that activation of the inflammasome pathway may play a role in disease progression. To test this, we studied the inflammasome molecular platform in dysferlin-deficient human and mouse muscle. Consistent with our model, components of the NACHT, LRR and PYD-containing proteins (NALP)-3 inflammasome pathway were specifically up-regulated and activated in dysferlin-deficient but not in dystrophin-deficient and normal muscle. We demonstrate for the first time that normal primary skeletal muscle cells are capable of secreting IL-1beta in response to combined treatment with lipopolysaccharide and the P2X7 receptor agonist, benzylated ATP, suggesting that not only immune cells but also muscle cells can actively participate in inflammasome formation. In addition, we show that dysferlin-deficient primary muscle cells express toll-like receptors (TLRs; TLR-2 and TLR-4) and can efficiently produce IL-1beta in response to lipopolysaccharide and benzylated ATP. These data indicate that skeletal muscle is an active contributor of IL-1beta and strategies that interfere with this pathway may be therapeutically useful for patients with limb girdle muscular dystrophy type 2B.American Journal Of Pathology 04/2010; 176(6):2891-900. · 4.89 Impact Factor
Article: Characterization of dysferlin deficient SJL/J mice to assess preclinical drug efficacy: fasudil exacerbates muscle disease phenotype.[show abstract] [hide abstract]
ABSTRACT: The dysferlin deficient SJL/J mouse strain is commonly used to study dysferlin deficient myopathies. Therefore, we systematically evaluated behavior in relatively young (9-25 weeks) SJL/J mice and compared them to C57BL6 mice to determine which functional end points may be the most effective to use for preclinical studies in the SJL/J strain. SJL/J mice had reduced body weight, lower open field scores, higher creatine kinase levels, and less muscle force than did C57BL6 mice. Power calculations for expected effect sizes indicated that grip strength normalized to body weight and open field activity were the most sensitive indicators of functional status in SJL/J mice. Weight and open field scores of SJL/J mice deteriorated over the course of the study, indicating that progressive myopathy was ongoing even in relatively young (<6 months old) SJL/J mice. To further characterize SJL/J mice within the context of treatment, we assessed the effect of fasudil, a rho-kinase inhibitor, on disease phenotype. Fasudil was evaluated based on previous observations that Rho signaling may be overly activated as part of the inflammatory cascade in SJL/J mice. Fasudil treated SJL/J mice showed increased body weight, but decreased grip strength, horizontal activity, and soleus muscle force, compared to untreated SJL/J controls. Fasudil either improved or had no effect on these outcomes in C57BL6 mice. Fasudil also reduced the number of infiltrating macrophages/monocytes in SJL/J muscle tissue, but had no effect on muscle fiber degeneration/regeneration. These studies provide a basis for standardization of preclinical drug testing trials in the dysferlin deficient SJL/J mice, and identify measures of functional status that are potentially translatable to clinical trial outcomes. In addition, the data provide pharmacological evidence suggesting that activation of rho-kinase, at least in part, may represent a beneficial compensatory response in dysferlin deficient myopathies.PLoS ONE 01/2010; 5(9):e12981. · 4.09 Impact Factor
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ABSTRACT: Repair of plasma membrane tears is an important normal physiological process that enables the cells to survive a variety of physiological and pathological membrane lesions. Dysferlin was the first protein reported to play a crucial role in this repair process in muscle, and recently, several other proteins including Mitsugumin 53 (MG53), annexin and calpain were also found to participate. These findings have now established the framework of the membrane repair mechanism. Defective membrane repair in dysferlin-deficient muscle leads to the development of muscular dystrophy associated with remarkable muscle inflammation. Recent studies have demonstrated a crosstalk between defective membrane repair and immunological attack, thus unveiling a new pathophysiological mechanism of dysferlinopathy. Here I summarize and discuss the latest progress in the molecular mechanisms of membrane repair and the pathogenesis of dysferlinopathy. Discussion about potential therapeutic applications of these findings is also provided.Skeletal muscle. 01/2011; 1(1):10.