LMNA mutations, skeletal muscle lipid metabolism, and insulin resistance.
BACKGROUND
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.


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.
Franz-Volhard Clinical Research Center at the Experimental and Clinical Research Center, University Hospital Charite Campus Buch and HELIOS Klinikum-Berlin, 13125 Berlin, Germany. michael.boschmann@charite.de
Michael
M
Boschmann
Stefan
S
Engeli
Cedric
C
Moro
Angelika
A
Luedtke
Frauke
F
Adams
Kerstin
K
Gorzelniak
Gabriele
G
Rahn
Anja
A
Mähler
Kerstin
K
Dobberstein
Antje
A
Krüger
Saskia
S
Schmidt
Simone
S
Spuler
Friedrich C
FC
Luft
Steven R
SR
Smith
Hartmut H-J
HH
Schmidt
Jens
J
Jordan
D000328:Adult; D001786:Blood Glucose / Q000378:metabolism; D002331:Carnitine / Q000031:analogs & derivatives / Q000378:metabolism; D002478:Cells, Cultured; D004734:Energy Metabolism / Q000235:genetics / Q000502:physiology; D005260:Female; D006003:Glycogen / Q000096:biosynthesis; D006801:Humans; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000235:genetics*; D034904:Lamin Type A / Q000235:genetics*; D050356:Lipid Metabolism / Q000235:genetics*; D052496:Lipodystrophy, Familial Partial / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000235:genetics / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D010084:Oxidation-Reduction; D010641:Phenotype
D001786:Blood Glucose; D007328:Insulin; C494847:LMNA protein, human; D034904:Lamin Type A; C116917:acylcarnitine; D006003:Glycogen; D002331:Carnitine