LMNA mutations, skeletal muscle lipid metabolism, and insulin resistance

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.

Figure 1

Oral GTT. Serum glucose (top), insulin (middle), and free fatty acids (FFA) (bottom) in FPLD patients (n = 10) and in control subjects (n = 10) before and during oral GTT. ***, P < 0.001 by ANOVA. (Conversion factors to convert to metric units (mg/dl) are as follows: 18.02 for glucose, 0.028 for nonesterified fatty acids).

Figure 2

Acylcarnitine profiling. Even chain plasma acylcarnitines from FPLD patients (n = 10) and control subjects (n = 10) after an overnight fast. *, P < 0.05; **, P < 0.01.

Figure 3

Substrate oxidation measured by indirect calorimetry. Energy expenditure (relative changes, upper panel) and RQ (lower panel) in FPLD patients (n = 10), a patient with LGMD1B, and control subjects (n = 10) before and during oral GTT. The reduced RQ value in FPLD patients and in the LGMD1B patient indicates increased fatty acid oxidation. The inability to increase RQ during glucose loading to normal values is indicative of metabolic inflexibility. *, P < 0.05; ***, P < 0.001 by ANOVA.

Figure 4

Skeletal muscle microdialysis. Ethanol ratio and dialysate concentrations of glucose, lactate, pyruvate, and glycerol in skeletal muscle in FPLD patients (n = 10) and in control subjects (n = 10) before and during oral GTT. **, P < 0.01; ***, P < 0.001 by ANOVA.

Figure 5

In vitro lipid oxidation. We applied carbon [1-¹⁴C]labeled palmitate to in vitro differentiated myoblasts from control subjects (n = 6), FPLD patients (n = 2; 40- and 52-yr-old females with a LMNA R482W and R482Q mutation, respectively), and a patient with LGMD1B (50-yr-old female with LMNA W498C mutations). ¹⁴CO₂ (upper panel) and ¹⁴C-ASM (lower panel) indicated complete and incomplete lipid oxidation, respectively. *, P < 0.05.