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Integrin‐Linked Kinase Enhances Skeletal Muscle Fatty Acid Metabolism In Vivo
Author(s) -
Lark Daniel S,
Trefts Elijah,
James Merrygay,
Zent Roy,
Pozzi Ambra,
Wasserman David H
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1014.10
Subject(s) - integrin linked kinase , insulin resistance , insulin receptor , medicine , endocrinology , skeletal muscle , integrin , peroxisome , chemistry , mitochondrial biogenesis , biology , biochemistry , kinase , insulin , mitochondrion , protein kinase a , receptor , cyclin dependent kinase 2
Accumulation of extracellular matrix (ECM) components and activation of specific integrin receptors contribute to skeletal muscle (SkM) insulin resistance in the high fat (HF)‐fed mouse. Integrin‐linked kinase (ILK) is an adaptor protein that serves as a hub for the integrin signaling but its role in metabolism is poorly defined. A shift from glucose to fatty acid (FA) oxidation is a hallmark of insulin resistance and diabetes, but the mechanisms responsible for this shift in nutrient utilization are unclear. Integrins have been implicated in the transcriptional regulation of mitochondrial biogenesis and are known to interact with FA transporters at the plasma membrane. The objective of this study was to test the novel hypothesis that integrins, through ILK signaling, enhance SkM FA metabolism under insulin resistant conditions. SkM‐specific ILK knockout mice (mILK‐KO) were generated using mice expressing Cre recombinase on the human SkM actin (HSA) promoter. Body weight was measured weekly and body composition was measured immediately prior to and following energy balance studies. mILK‐KO and their wild type (WT) littermates were fed a chow or HF diet (60% calories from fat) for 27 weeks then placed in metabolic cages for five days (n=6–9/group). Tissues were collected after a 5‐h fast. Pyruvate and FA‐supported mitochondrial respiratory capacity was measured in permeabilized SkM myofibers (PmFBs) from the soleus and EDL. Muscle free fatty acids (FFAs) and triglycerides (TGs) were measured in gastrocnemius with gas chromatography. Comparisons were made using Student's t‐test or 2‐way ANOVA as appropriate. HF‐fed mILK‐KO mice had a decreased reliance on FA oxidation compared to their WT littermates, as suggested by the increase in RQ. This RQ difference was independent of changes in whole body energy expenditure, body composition, food consumption or spontaneous activity. RQ was unchanged in mILK‐KO mice fed a chow diet. FA‐supported PmFB respiration was decreased in EDL, but not soleus, of HF‐fed mILK‐KO mice. Respiration in chow‐fed mice was not affected by muscle ILK deletion. Total muscle FFAs and TGs were increased by HF feeding but lower in mILK‐KO mice fed a HF diet. Muscle lipids were unaffected by ILK deletion in mice on a chow diet. These data are the first to demonstrate a mechanistic role for integrin signaling in the regulation of SkM FA metabolism in vivo and suggest that integrin signaling, through ILK, responds to nutrient overload by enhancing the uptake, storage and oxidation of FAs in SkM. These findings provide strong support for a model where extracellular cues (e.g. ECM expansion) cause a coordinated shift in cellular energetics, a paradigm that may permit for therapeutic targeting of oxidative metabolism through integrin receptors. Support or Funding Information Funding for this project was provided by the following NIH grants: R01 DK054902, U24 DK059637, P30 DK020593 , and T32 DK007061.