glycogen and Muscular-Dystrophies--Limb-Girdle

Caveolin-3 (CAV3) is a muscle specific protein that plays an important role in maintaining muscle health and glucose homeostasis in vivo. A novel autosomal dominant form of LGMD-1C in humans is due to a P104L mutation within the coding sequence of the human CAV3 gene. The mechanism by which the LGMD-1C mutation leads to muscle weakness remains unknown. Our objective was to determine whether muscle weakness was related to the imbalance of glucose metabolism. We found that when the P104L mutation was transiently transfected into C2C12 cells, there was decreased glucose uptake and glycogen synthesis after insulin stimulation. Immunoblotting analysis showed that the P104L mutation resulted in decreased expression of CAV3, CAV1 and pAkt. Confocal immunomicroscopy indicated that the P104L mutation reduced CAV3 and GLUT4 in the cell membrane, which accumulated mainly near the nucleus. This work is the first report of an association between muscle weakness due to LGMD-1C and energy metabolism. The P104L mutation led to a decrease in C2C12 muscle glucose uptake and glycogen synthesis and may be involved in the pathogenesis of LGMD-1C.

Topics: Amino Acid Sequence; Animals; Caveolin 1; Caveolin 3; Cell Differentiation; Cell Line; Cell Membrane; Gene Expression Regulation; Genes, Reporter; Glucose; Glucose Transporter Type 4; Glycogen; Green Fluorescent Proteins; Humans; Insulin; Mice; Muscle Cells; Muscular Dystrophies, Limb-Girdle; Mutation; Myoblasts; Protein Structure, Secondary; Proto-Oncogene Proteins c-akt; Signal Transduction; Transgenes

Pompe disease (glycogen storage disease type 2 or acid maltase deficiency) is a rare autosomal recessive lysosomal storage disorder. Since the advent of ERT a lot has been learned about the phenotypic spectrum especially in the late onset patients. We describe in detail 44 patients diagnosed with late-onset Pompe disease (LOPD) at our neuromuscular department from 1985 to 2011 and compare them to patients with LOPD in the literature of the past 40 years. Study of the Munich LOPD group revealed varying musculoskeletal and cardio-cerebrovascular manifestation patterns. Several of these symptom patterns commonly appeared in conjunction with one another, highlighting the multisystem involvement of this condition. Common symptom patterns include: (i) Classic limb girdle and diaphragmatic weakness, (ii) rigid spine syndrome (RSS), scoliosis, and low body mass, and (iii) several cardio-cerebrovascular manifestation patterns. The most common presentation, limb girdle and diaphragmatic weakness, appeared in 78% (34/44) of our patients and over 80% of those in the literature. Sixteen percent (7/44) of our patients presented with rigid spine, scoliosis, and low body mass. Although scoliosis had a reported frequency of 33% in the general LOPD patient population, the literature only occasionally reported low body mass and RSS. Importantly, a multisystem extramuscular finding accompanied by cardio-cerebrovascular manifestations was found in 29% (13/44) of our LOPD patients; the literature showed an increasing prevalence of this latter finding. By examining the phenotype of patients with confirmed LOPD, we found a more subtle clinical multisystem involvement in LOPD. Whether patients presenting with the different symptom patterns respond differently to enzyme replacement therapy remains a key question for future research. © 2012 Wiley Periodicals, Inc.

Topics: Adolescent; Adult; Age of Onset; Aged; Cardiovascular Abnormalities; Cerebrovascular Disorders; Child; Female; Glycogen; Glycogen Storage Disease Type II; Humans; Male; Mallory Bodies; Middle Aged; Muscular Dystrophies; Muscular Dystrophies, Limb-Girdle; Musculoskeletal Abnormalities; Phenotype; Scoliosis

Topics: Adult; Diagnosis, Differential; Female; Glycogen; Glycogen Storage Disease Type II; Humans; Liver; Muscle, Skeletal; Muscular Dystrophies, Limb-Girdle; Pyomyositis; Young Adult

Type 2 familial partial lipodystrophy (FPLD) is an autosomal-dominant lamin A/C-related disease associated with exercise intolerance, muscular pain, and insulin resistance. The symptoms may all be explained by defective metabolism; however, metabolism at the tissue level has not been investigated.. We hypothesized that in FPLD, insulin resistance and impaired aerobic exercise capacity are explained by a common underlying mechanism, presumably a muscular metabolic defect.. Carbohydrate and lipid metabolism was studied on 10 FPLD patients, one patient with limb-girdle muscular dystrophy (LGMD1B, a different lamin A/C disease), and 10 healthy control subjects before and during an oral glucose tolerance test by indirect calorimetry and im microdialysis. Muscle biopsies were taken for in vitro studies.. We observed marked increased skeletal muscle fatty acid beta-oxidation rate in vitro and in vivo, even after glucose ingestion in FPLD patients. However, fatty acid oxidation was largely incomplete and accompanied by increased ketogenesis. The lipid oxidation abnormality was associated with impaired glucose disposition through reduction in glucose oxidation, rather than decreased cellular glucose uptake. A microarray showed down-regulation of complex I respiratory chain, glycolysis, and nuclear transport genes. Although not overtly insulin resistant, the LGMD1B patient showed similar metabolic derangements as the FPLD patients.. Our study suggests imbalance between lipid oxidation and oxidative glucose metabolism in FPLD and LGMD1B patients. The observation suggests an intrinsic defect in skeletal muscle metabolism due to lamin A/C dysfunction. The metabolic FPLD phenotype likely results from this intrinsic defect combined with lipodystrophic "lipid pressure" due to decreased adipose tissue lipid storage capacity.

Topics: Adult; Blood Glucose; Carnitine; Cells, Cultured; Energy Metabolism; Female; Glycogen; Humans; Insulin; Insulin Resistance; Lamin Type A; Lipid Metabolism; Lipodystrophy, Familial Partial; Male; Middle Aged; Muscle Fibers, Skeletal; Muscle, Skeletal; Muscular Dystrophies, Limb-Girdle; Mutation; Oligonucleotide Array Sequence Analysis; Oxidation-Reduction; Phenotype