Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026850 (muscular dystrophy)
 5,870 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Serious diabetic complications affect millions of patients worldwide. Skeletal muscle represents the largest insulin-regulated glucose sink in the body, making insulin resistance and abnormal glucose disposal in muscle fibres a critical aspect of diabetes mellitus. Advances in the biomedical analysis of the molecular mechanisms underlying diabetic complications rely heavily on the study of suitable disease models. The Goto-Kakizaki (GK) rat is an established animal model of non-obese type 2 diabetes. This review discusses the recent finding that expression of the dystrophin-dystroglycan complex is drastically altered in diabetic GK skeletal muscle fibres. In normal muscle, the dystrophin-glycoprotein complex provides a stabilizing connection between the actin membrane cytoskeleton and the extracellular matrix component laminin. A reduction in dystrophin-associated proteins may be associated with a weakening of the fibre periphery, abnormal sarcolemmal signaling and/or a decreased cytoprotective mechanism in diabetic skeletal muscle. Stimulation by insulin might be altered due to impaired linkage between the dystrophin-anchored actin cytoskeleton and the intracellular pool of essential glucose transporters. The diminished recruitment of GLUT4 transporter molecules to the sarcolemma may be a key step in the development of insulin resistance in diabetic skeletal muscles. Thus, analogous to certain forms of muscular dystrophy, altered dystrophin levels may have pathological effects in type 2 diabetes. In contrast, the dystrophin-glycoprotein complex does not appear to be altered in diabetic cardiac muscle. However, reduced expression of the sarcoplasmic reticulum Ca2+-ATPase isoform SERCA2 is characteristic of cardiac abnormalities in type 2 diabetes. Reduced Ca2+ removal from the sarcoplasm may be associated with impaired relaxation kinetics, and could therefore play a pathophysiological role in diabetic cardiomyopathy. Here, the potential impact of these molecular alterations in diabetic muscle tissues is discussed and critically examined with respect to the future design of alternative treatment strategies to counteract diabetes-associated muscle weakness.
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PMID:The pathobiochemical role of the dystrophin-dystroglycan complex and the Ca2+-handling apparatus in diabetes-related muscle weakness (Review). 2147 10

Limb-girdle muscular dystrophy type 2A (LGMD2A) is a form of muscular dystrophy caused by mutations in calpain 3 (CAPN3). Several studies have implicated Ca2+ dysregulation as an underlying event in several muscular dystrophies, including LGMD2A. In this study we used mouse and human myotube cultures, and muscle biopsies in order to determine whether dysfunction of sarco/endoplasmatic Ca2+-ATPase (SERCA) is involved in the pathology of this disease. In CAPN3-deficient myotubes, we found decreased levels of SERCA 1 and 2 proteins, while mRNA levels remained comparable with control myotubes. Also, we found a significant reduction in SERCA function that resulted in impairment of Ca2+ homeostasis, and elevated basal intracellular [Ca2+] in human myotubes. Furthermore, small Ankyrin 1 (sAnk1), a SERCA1-binding protein that is involved in sarcoplasmic reticulum integrity, was also diminished in CAPN3-deficient fibres. Interestingly, SERCA2 protein was patently reduced in muscles from LGMD2A patients, while it was normally expressed in other forms of muscular dystrophy. Thus, analysis of SERCA2 expression may prove useful for diagnostic purposes as a potential indicator of CAPN3 deficiency in muscle biopsies. Altogether, our results indicate that CAPN3 deficiency leads to degradation of SERCA proteins and Ca2+ dysregulation in the skeletal muscle. While further studies are needed in order to elucidate the specific contribution of SERCA towards muscle degeneration in LGMD2A, this study constitutes a reasonable foundation for the development of therapeutic approaches targeting SERCA1, SERCA2 or sAnk1.
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PMID:Calpain 3 deficiency affects SERCA expression and function in the skeletal muscle. 2705


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