Dataset Information

Association of the CPT1B gene with skeletal muscle fat infiltration in Afro-Caribbean men.

ABSTRACT: Skeletal muscle fat is greater in African ancestry individuals compared with whites, is associated with diabetes, and is a heritable polygenic trait. However, specific genetic factors contributing to skeletal muscle fat in humans remain to be defined. Muscle carnitine palmitoyltransferase-1B (CPT1B) is a key enzyme in the regulation of skeletal muscle mitochondrial beta-oxidation of long-chain fatty acids, and as such is a reasonable biological candidate gene for skeletal muscle fat accumulation. Therefore, we examined the association of three nonsynonymous coding variants in CPT1B (G531L, I66V, and S427C; a fourth, A320G, could not be genotyped) and quantitative computed tomography measured tibia skeletal muscle composition and BMI among 1,774 Afro-Caribbean men aged > or =40, participants of the population-based Tobago Health Study. For all variants, no significant differences were observed for BMI or total adipose tissue. Among individuals who were homozygous for the minor allele at G531L or I66V, intermuscular adipose tissue (IMAT) was 87% (P = 0.03) and 54% lower (P = 0.03), respectively. In contrast, subcutaneous adipose tissue (SAT) was 11% (P = 0.017) and 7% (P = 0.049) higher, respectively, than among individuals without these genotypes. These associations were independent of age, body size, and muscle area. Finally, no individuals with type 2 diabetes were found among those who were homozygous for the minor allele of either at G531L and I66V whereas 14-18% of men with the major alleles had type 2 diabetes (P = 0.03 and 0.007, respectively). Our results suggest a novel association between common nonsynonymous coding variants in CPT1B and ectopic skeletal muscle fat among middle-aged and older African ancestry men.

SUBMITTER: Miljkovic I

PROVIDER: S-EPMC2895554 | biostudies-other | 2009 Jul

REPOSITORIES: biostudies-other

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Association of the CPT1B gene with skeletal muscle fat infiltration in Afro-Caribbean men.

Miljkovic Iva I Yerges Laura M LM Li Hu H Gordon Christopher L CL Goodpaster Bret H BH Kuller Lewis H LH Nestlerode Cara S CS Bunker Clareann H CH Patrick Alan L AL Wheeler Victor W VW Zmuda Joseph M JM

Obesity (Silver Spring, Md.) 20090219 7

Skeletal muscle fat is greater in African ancestry individuals compared with whites, is associated with diabetes, and is a heritable polygenic trait. However, specific genetic factors contributing to skeletal muscle fat in humans remain to be defined. Muscle carnitine palmitoyltransferase-1B (CPT1B) is a key enzyme in the regulation of skeletal muscle mitochondrial beta-oxidation of long-chain fatty acids, and as such is a reasonable biological candidate gene for skeletal muscle fat accumulation ...[more]

PMID: 19553926

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Project description:BackgroundAgeing is accompanied by sarcopenia and intramuscular fat (IMAT) infiltration. In skeletal muscle, fat infiltration is a common feature in several myopathies and is associated with muscular dysfunction and insulin resistance. However, the cellular origin and lipidomic and transcriptomic changes during fat infiltration in skeletal muscle remain unclear.MethodsIn the current study, we generated a high IMAT-infiltrated skeletal muscle model by glycerol (GLY) injection. Single-cell RNA sequencing and lineage tracing were performed on GLY-injured skeletal muscle at 5 days post-injection (DPI) to identify the cell origins and dynamics. Lipidomics and RNA sequencing were performed on IMAT-infiltrated skeletal muscle at 14 DPI (or 17 DPI for the cold treatment) to analyse alterations of lipid compositions and gene expression levels.ResultsWe identified nine distinct major clusters including myeloid-derived cells (52.13%), fibroblast/fibro/adipogenic progenitors (FAPs) (23.24%), and skeletal muscle stem cells (2.02%) in GLY-injured skeletal muscle. Clustering and pseudotemporal trajectories revealed six subpopulations in fibroblast/FAPs and 10 subclusters in myeloid-derived cells. A subpopulation of myeloid-derived cells expressing adipocyte-enriched genes and Pdgfra- /Cd68+ cells displayed lipid droplets upon adipogenic induction, indicating their adipogenic potential. Lipidomic analysis revealed the changes of overall lipid classes composition (e.g. triglycerides (TAGs) increased by 19.3 times, P = 0.0098; sulfoquinovosyl diacylglycerol decreased by 83%, P = 0.0056) and in the distribution of lipids [e.g. TAGs (18:2/18:2/22:6) increased by 181.6 times, P = 0.021] between GLY-group and saline control. RNA-seq revealed 1847 up-regulated genes and 321 down-regulated genes and significant changes in lipid metabolism-related pathways (e.g. glycerolipid pathway and glycerophospholipid pathway) in our model of GLY-injured skeletal muscle. Notably, short-term cold exposure altered fatty acid composition (e.g. saturated fatty acid decreased by 6.4%, P = 0.058) in fat-infiltrated muscles through directly affecting lipid metabolism pathways including PI3K-AKT and MAPK signalling pathway.ConclusionsOur results showed that a subpopulation of myeloid-derived cells may contribute to IMAT infiltration. GLY-induced IMAT infiltration changed the lipid composition and gene expression profiles. Short-term cold exposure might regulate lipid metabolism and its related signalling pathways in fat-infiltrated muscle. Our study provides a comprehensive resource describing the molecular signature of fat infiltration in skeletal muscle.

Project description:Limited numbers of studies demonstrated obesity-induced macrophage infiltration in skeletal muscle (SM), but dynamics of immune cell accumulation and contribution of T cells to SM insulin resistance are understudied.T cells and macrophage markers were examined in SM of obese humans by reverse transcription-PCR (RT-PCR). Mice were fed high-fat diet (HFD) for 2-24 weeks, and time course of macrophage and T-cell accumulation was assessed by flow cytometry and quantitative RT-PCR. Extramyocellular adipose tissue (EMAT) was quantified by high-resolution micro-computed tomography (CT), and correlation to T-cell number in SM was examined. CD11a-/- mice and C57BL/6 mice were treated with CD11a-neutralizing antibody to determine the role of CD11a in T-cell accumulation in SM. To investigate the involvement of Janus kinase/signal transducer and activator of transcription (JAK/STAT), the major pathway for T helper I (TH1) cytokine interferon-?, in SM and adipose tissue inflammation and insulin resistance, mice were treated with a JAK1/JAK2 inhibitor, baricitinib.Macrophage and T-cell markers were upregulated in SM of obese compared with lean humans. SM of obese mice had higher expression of inflammatory cytokines, with macrophages increasing by 2 weeks on HFD and T cells increasing by 8 weeks. The immune cells were localized in EMAT. Micro-CT revealed that EMAT expansion in obese mice correlated with T-cell infiltration and insulin resistance. Deficiency or neutralization of CD11a reduced T-cell accumulation in SM of obese mice. T cells polarized into a proinflammatory TH1 phenotype, with increased STAT1 phosphorylation in SM of obese mice. In vivo inhibition of JAK/STAT pathway with baricitinib reduced T-cell numbers and activation markers in SM and adipose tissue and improved insulin resistance in obese mice.Obesity-induced expansion of EMAT in SM was associated with accumulation and proinflammatory polarization of T cells, which may regulate SM metabolic functions through paracrine mechanisms. Obesity-associated SM 'adiposopathy' may thus have an important role in the development of insulin resistance and inflammation.

Project description:Key pointsMuscle infiltration with adipose tissue (IMAT) is common and associated with loss of skeletal muscle strength and physical function across a diverse set of pathologies. Whether the association between IMAT and muscle weakness is causative or simply correlative remains an open question that needs to be addressed to effectively guide muscle strengthening interventions in people with increased IMAT. In the present studies, we demonstrate that IMAT deposition causes decreased muscle strength using mouse models. These findings indicate IMAT is a novel therapeutic target for muscle dysfunction.AbstractIntramuscular adipose tissue (IMAT) is associated with deficits in strength and physical function across a wide array of conditions, from injury to ageing to metabolic disease. Due to the diverse aetiologies of the primary disorders involving IMAT and the strength of the associations, it has long been proposed that IMAT directly contributes to this muscle dysfunction. However, infiltration of IMAT and reduced strength could both be driven by muscle disuse, injury and systemic disease, making IMAT simply an 'innocent bystander.' Here, we utilize novel mouse models to evaluate the direct effect of IMAT on muscle contraction. First, we utilize intramuscular glycerol injection in wild-type mice to evaluate IMAT in the absence of systemic disease. In this model we find that, in isolation from the neuromuscular and circulatory systems, there remains a muscle-intrinsic association between increased IMAT volume and decreased contractile tension (r2 > 0.5, P < 0.01) that cannot be explained by reduction in contractile material. Second, we utilize a lipodystrophic mouse model which cannot generate adipocytes to 'rescue' the deficits. We demonstrate that without IMAT infiltration, glycerol treatment does not reduce contractile force (P > 0.8). Taken together, this indicates that IMAT is not an inert feature of muscle pathology but rather has a direct impact on muscle contraction. This finding suggests that novel strategies targeting IMAT may improve muscle strength and function in a number of populations.

Dataset Information

Association of the CPT1B gene with skeletal muscle fat infiltration in Afro-Caribbean men.

Publications

Association of the CPT1B gene with skeletal muscle fat infiltration in Afro-Caribbean men.

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