LMNA Mutations, Skeletal Muscle Lipid Metabolism, and Insulin Resistance

Author:

Boschmann Michael1,Engeli Stefan2,Moro Cedric3,Luedtke Angelika4,Adams Frauke1,Gorzelniak Kerstin1,Rahn Gabriele1,Mähler Anja1,Dobberstein Kerstin1,Krüger Antje1,Schmidt Saskia5,Spuler Simone5,Luft Friedrich C.1,Smith Steven R.3,Schmidt Hartmut H.-J.6,Jordan Jens2

Affiliation:

1. Franz-Volhard Clinical Research Center at the Experimental and Clinical Research Center (M.B., F.A., K.G., G.R., A.M., K.D., A.K., F.C.L.), University Hospital Charité Campus Buch and HELIOS Klinikum-Berlin, 13125 Berlin, Germany

2. Institute of Clinical Pharmacology (S.E., J.J.), Hannover Medical School, 30625 Hannover, Germany

3. Pennington Biomedical Research Center (C.M., S.R.S.), Louisiana State University System, Baton Rouge, Louisiana 70808

4. Departments of Medicine and Anatomy and Cell Biology (A.L.), College of Physicians and Surgeons, Columbia University, New York, New York 10032

5. Myology Research Group at the Experimental & Clinical Research Center (S.Sc., S.Sp.), University Hospital Charité Campus Buch, 13125 Berlin, Germany

6. Department of Internal Medicine B (H.H.-J.S.), Westfälische Wilhelms-Universität Münster, 48149 Münster, Germany

Abstract

Abstract Context: 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. Objective: We hypothesized that in FPLD, insulin resistance and impaired aerobic exercise capacity are explained by a common underlying mechanism, presumably a muscular metabolic defect. Patients and Methods: 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. Results: We observed marked increased skeletal muscle fatty acid β-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. Conclusions: 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.

Publisher

The Endocrine Society

Subject

Biochemistry, medical,Clinical Biochemistry,Endocrinology,Biochemistry,Endocrinology, Diabetes and Metabolism

Reference39 articles.

1. Nuclear lamin A/C R482Q mutation in Canadian kindreds with Dunnigan-type familial partial lipodystrophy;Cao;Hum Mol Genet,2000

2. Mutational and haplotype analyses of families with familial partial lipodystrophy (Dunnigan variety) reveal recurrent missense mutations in the globular C-terminal domain of lamin A/C;Speckman;Am J Hum Genet,2000

3. LMNA, encoding lamin A/C, is mutated in partial lipodystrophy;Shackleton;Nat Genet,2000

4. Heterogeneity of nuclear lamin A mutations in Dunnigan-type familial partial lipodystrophy;Hegele;J Clin Endocrinol Metab,2000

5. The nuclear lamina comes of age;Gruenbaum;Nat Rev Mol Cell Biol,2005

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