A PGC-1α- and muscle fibre type-related decrease in markers of mitochondrial oxidative metabolism in skeletal muscle of humans with inherited insulin resistance

Kristensen, Jonas M.; Skov, Vibe; Petersson, Stine Juhl; Ørtenblad, Niels; Wojtaszewski, Jørgen F. P.; Beck‐Nielsen, Henning; Højlund, Kurt

doi:10.1007/s00125-014-3187-y

Cited by 34 publications

(28 citation statements)

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“…1A). This fiber type composition is in accordance with previous observations using (immuno)histochemistry (9-11,13-15,26) and biochemical methods (18,22). In the T2D group, MHC I, IIa, and IIx constituted 35, 45, and 20% (total 65% MHC II), respectively.…”

Section: Fiber Type Compositionsupporting

confidence: 92%

“…Thus, it is likely that human type I fibers are more important than type II fibers for maintaining glucose homeostasis in response to insulin. Indeed, a decreased proportion of type I fibers has been found in various insulin resistant states such as the metabolic syndrome (9), obesity (13,14), T2D in some (10,13,14) but not all (12,15) studies and following bedrest (16), as well as in tetraplegic patients (17), and subjects with an insulin receptor gene mutation (18).…”

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confidence: 99%

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Human Muscle Fiber Type–Specific Insulin Signaling: Impact of Obesity and Type 2 Diabetes

et al. 2014

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Skeletal muscle is a heterogeneous tissue composed of different fiber types. Studies suggest that insulinmediated glucose metabolism is different between muscle fiber types. We hypothesized that differences are due to fiber type-specific expression/regulation of insulin signaling elements and/or metabolic enzymes. Pools of type I and II fibers were prepared from biopsies of the vastus lateralis muscles from lean, obese, and type 2 diabetic subjects before and after a hyperinsulinemiceuglycemic clamp. Type I fibers compared with type II fibers have higher protein levels of the insulin receptor, GLUT4, hexokinase II, glycogen synthase (GS), and pyruvate dehydrogenase-E1a (PDH-E1a) and a lower protein content of Akt2, TBC1 domain family member 4 (TBC1D4), and TBC1D1. In type I fibers compared with type II fibers, the phosphorylation response to insulin was similar (TBC1D4, TBC1D1, and GS) or decreased (Akt and PDH-E1a). Phosphorylation responses to insulin adjusted for protein level were not different between fiber types. Independently of fiber type, insulin signaling was similar (TBC1D1, GS, and PDH-E1a) or decreased (Akt and TBC1D4) in muscle from patients with type 2 diabetes compared with lean and obese subjects. We conclude that human type I muscle fibers compared with type II fibers have a higher glucose-handling capacity but a similar sensitivity for phosphoregulation by insulin.Skeletal muscle is important for whole-body insulinstimulated glucose disposal (1), and skeletal muscle insulin resistance is a common phenotype of obesity and type 2 diabetes (T2D) (2). Skeletal muscle is a heterogeneous tissue composed of different fiber types, which can be divided according to myosin heavy chain (MHC) isoform expression. Studies in rodents show that insulin-stimulated glucose uptake in the oxidative type I fiber-dominant muscles is higher than in muscles with a high degree of glycolytic type II fibers (3-6). Whether this phenomenon is due to differences in locomotor activity of individual muscles or a direct consequence of the fiber-type composition is largely unknown. In incubated rat muscle, insulin-induced glucose uptake was higher (;100%) in type IIa (oxidative/glycolytic) compared with IIx and IIb (glycolytic) fibers (7,8), suggesting that insulin-mediated glucose uptake is related to the oxidative capacity of the muscle fiber. In humans, a positive correlation between proportions of type I fibers in muscle and whole-body insulin sensitivity has been demonstrated (9-11). Furthermore, insulin-stimulated glucose transport in human muscle strips was associated with the relative type I fiber content (12). Thus, it is likely that human type I fibers are more important than type II fibers for maintaining glucose homeostasis in response to insulin. Indeed, a decreased proportion of type I fibers has been found in various insulin resistant states such as the metabolic syndrome (9), obesity (13,14), T2D in some (10,13,14) but not all (12,15) studies and following bedrest (16), as well as in tetraplegic patients (17), ...

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Section: Fiber Type Compositionsupporting

confidence: 92%

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confidence: 99%

Human Muscle Fiber Type–Specific Insulin Signaling: Impact of Obesity and Type 2 Diabetes

et al. 2014

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“…Alleviating mitochondrial dysfunction may decrease cardiac I/R injury. Meanwhile, modulating mitochondrial function may improve insulin resistance and reduce subsequent cardiac mortality 23,24. In the present study, lin28a overexpression alleviated mitochondria ultrastructure impairment as demonstrated by intact membrane and cristae although still with a greater size after cardiac I/R in diabetic mice.…”

Section: Discussionsupporting

confidence: 53%

Lin28a protects against cardiac ischaemia/reperfusion injury in diabetic mice through the insulin‐PI3K‐mTOR pathway

Zhang

Sun

et al. 2015

J Cellular Molecular Medi

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The insulin-PI3K-mTOR pathway exhibits a variety of cardiovascular activities including protection against I/R injury. Lin28a enhanced glucose uptake and insulin-sensitivity via insulin-PI3K-mTOR signalling pathway. However, the role of lin28a on experimental cardiac I/R injury in diabetic mice are not well understood. Diabetic mice underwent 30 min. of ischaemia followed by 3 hrs of reperfusion. Animals were randomized to be treated with lentivirus carrying lin28a siRNA (siLin28a) or lin28a cDNA (Lin28a) 72 hrs before coronary artery ligation. Myocardial infarct size (IS), cardiac function, cardiomyocyte apoptosis and mitochondria morphology in diabetic mice who underwent cardiac I/R injury were compared between groups. The target proteins of lin28a were examined by western blot analysis. Lin28a overexpression significantly reduced myocardial IS, improved LV ejection fraction (LVEF), decreased myocardial apoptotic index and alleviated mitochondria cristae destruction in diabetic mice underwent cardiac I/R injury. Lin28a knockdown exacerbated cardiac I/R injury as demonstrated by increased IS, decreased LVEF, increased apoptotic index and aggravated mitochondria cristae destruction. Interestingly, pre-treatment with rapamycin abolished the beneficial effects of lin28a overexpression. Lin28a overexpression increased, while Lin28a knockdown decreased the expression of IGF1R, p-Akt, p-mTOR and p-p70s6k after cardiac I/R injury in diabetic mice. Rapamycin pre-treatment abolished the effects of increased p-mTOR and p-p70s6k expression exerted by lin28a overexpression. This study indicates that lin28a overexpression reduces IS, improves cardiac function, decreases cardiomyocyte apoptosis index and alleviates cardiomyocyte mitochondria impairment after cardiac I/R injury in diabetic mice. The mechanism responsible for the effects of lin28a is associated with the insulin-PI3K-mTOR dependent pathway.

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“…Finally, we performed a principal component analysis on the entire gene expression signature of our control and experimental samples (EPC, UASMC, iSMC) as well as control samples from previously published studies: Skeletal Muscle 24,25 , Brain 26 , Liver 26 , Umbilical Vein and Coronary Artery Endothelial Cells 27 , Aortic Smooth Muscle Cells 28,29 , Dermal Fibroblasts 30 . This analysis confirmed that the transdifferentiated iSMC closely resemble the control cells including adult aorta SMC and umbilical artery SMC while at the same time being significantly different from the starting EPC population (Figure 3G).…”

Section: Resultsmentioning

confidence: 99%

Transdifferentiation of human endothelial progenitors into smooth muscle cells

Atchison

Chen

et al. 2016

Biomaterials

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Access to smooth muscle cells (SMC) would create opportunities for tissue engineering, drug testing, and disease modeling. Herein we report the direct conversion of human endothelial progenitor cells (EPC) to induced smooth muscle cells (iSMC) by induced expression of MYOCD. The EPC undergo a cytoskeletal rearrangement resembling that of mesenchymal cells within 3 days post initiation of MYOCD expression. By day 7, the reprogrammed cells show upregulation of smooth muscle markers ACTA2, MYH11, and TAGLN by qRT-PCR and ACTA2 and MYH11 expression by immunofluorescence. By two weeks, they resemble umbilical artery SMC in microarray gene expression analysis. The iSMC, in contrast to EPC control, show calcium transients in response to phenylephrine stimulation and a contractility an order of magnitude higher than that of EPC as determined by traction force microscopy. Tissue-engineered blood vessels constructed using iSMC show functionality with respect to flow- and drug-mediated vasodilation and vasoconstriction.

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A PGC-1α- and muscle fibre type-related decrease in markers of mitochondrial oxidative metabolism in skeletal muscle of humans with inherited insulin resistance

Abstract: These data indicate that inherited insulin resistance coincides with reduced mitochondrial oxidative capacity in a PGC-1α- and muscle fibre type-related manner. Whether this co-existence is directly or indirectly related to insulin resistance remains to be elucidated.

Cited by 34 publications

References 49 publications

Human Muscle Fiber Type–Specific Insulin Signaling: Impact of Obesity and Type 2 Diabetes

Human Muscle Fiber Type–Specific Insulin Signaling: Impact of Obesity and Type 2 Diabetes

Lin28a protects against cardiac ischaemia/reperfusion injury in diabetic mice through the insulin‐PI3K‐mTOR pathway

Transdifferentiation of human endothelial progenitors into smooth muscle cells

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