LMNA mutations, skeletal muscle lipid metabolism, and insulin resistance

J Clin Endocrinol Metab. 2010 Apr;95(4):1634-43. doi: 10.1210/jc.2009-1293. Epub 2010 Feb 3.

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 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.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Blood Glucose / metabolism
  • Carnitine / analogs & derivatives
  • Carnitine / metabolism
  • Cells, Cultured
  • Energy Metabolism / genetics
  • Energy Metabolism / physiology
  • Female
  • Glycogen / biosynthesis
  • Humans
  • Insulin / blood
  • Insulin Resistance / genetics*
  • Lamin Type A / genetics*
  • Lipid Metabolism / genetics*
  • Lipodystrophy, Familial Partial / genetics*
  • Lipodystrophy, Familial Partial / metabolism*
  • Male
  • Middle Aged
  • Muscle Fibers, Skeletal / metabolism
  • Muscle, Skeletal / metabolism*
  • Muscular Dystrophies, Limb-Girdle / genetics
  • Muscular Dystrophies, Limb-Girdle / metabolism
  • Mutation / genetics
  • Mutation / physiology*
  • Oligonucleotide Array Sequence Analysis
  • Oxidation-Reduction
  • Phenotype

Substances

  • Blood Glucose
  • Insulin
  • LMNA protein, human
  • Lamin Type A
  • acylcarnitine
  • Glycogen
  • Carnitine