Disrupted glucose homeostasis and skeletal-muscle-specific glucose uptake in an exocyst knockout mouse model

Fujimoto, B.; Young, Madison; Nakamura, Nicole; Ha, Herena Y.; Carter, Lamar; Pitts, Michael R.; Torres, Daniel J.; Noh, Hye Lim; Suk, Sujin; Kim, Jason K.; Polgár, Noémi

doi:10.1016/j.jbc.2021.100482

Cited by 14 publications

(12 citation statements)

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“…Keywords: interleukin-6, muscle atrophy, transcription factor, energy metabolism, inflammation BACKGROUND Skeletal muscle homeostasis refers to the balance between anabolism and catabolism in response to endogenous and exogenous stimuli and enables maintaining movement ability in mammals (1,2). Skeletal muscles have strong plasticity, and consistent physical exercise can increase muscle mass and muscle strength.…”

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confidence: 99%

Transcriptome Analysis of Immune Receptor Activation and Energy Metabolism Reduction as the Underlying Mechanisms in Interleukin-6-Induced Skeletal Muscle Atrophy

Sun

et al. 2021

Front. Immunol.

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BackgroundInflammation may trigger skeletal muscle atrophy induced by cancer cachexia. As a pro-inflammatory factor, interleukin-6 may cause skeletal muscle atrophy, but the underlying molecular mechanisms have not been explored.MethodsIn this experimental study, we used adult male ICR mice, weighing 25 ± 2 g, and the continuous infusion of interleukin-6 into the tibialis anterior muscle to construct a skeletal muscle atrophy model (experimental group). A control group received a saline infusion. RNA-sequencing was used to analyze the differentially expressed genes in tissue samples after one and three days. Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes analysis were applied to define the function of these genes, and protein-protein interaction analysis was performed to identify potential transcription factors. Fluorescence microscopy was used to determine the muscle fiber cross-sectional area after 14 days.ResultsContinuous infusion of interleukin-6 for 14 days caused significant muscle atrophy. RNA-sequencing found 359 differentially expressed genes in the 1- and 3-day tissue samples and 1748 differentially expressed genes only in the 3-day samples. Functional analysis showed that the differentially expressed genes found in both the 1- and 3-day samples were associated with immune receptor activation, whereas the differentially expressed genes found only in the 3-day sample were associated with reduced energy metabolism. The expression of multiple genes in the oxidative phosphorylation and tricarboxylic acid cycle pathways was down-regulated. Furthermore, differentially expressed transcription factors were identified, and their interaction with interleukin-6 and the differentially expressed genes was predicted, which indicated that STAT3, NF-κB, TP53 and MyoG may play an important role in the process of interleukin-6-induced muscle atrophy.ConclusionsThis study found that interleukin-6 caused skeletal muscle atrophy through immune receptor activation and a reduction of the energy metabolism. Several transcription factors downstream of IL-6 have the potential to become new regulators of skeletal muscle atrophy. This study not only enriches the molecular regulation mechanism of muscle atrophy, but also provides a potential target for targeted therapy of muscle atrophy.

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confidence: 99%

Transcriptome Analysis of Immune Receptor Activation and Energy Metabolism Reduction as the Underlying Mechanisms in Interleukin-6-Induced Skeletal Muscle Atrophy

Sun

et al. 2021

Front. Immunol.

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“…Next, we examined whether alteration in glucose uptake by skeletal muscle, which accounts for 80% to 90% of glucose uptake in the postprandial state ( 37 , 38 ) could result in the enhanced glucose excursion seen in HFD-fed HKDC1 Int–/– mice. We assessed mouse gastrocnemius ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Enterocyte HKDC1 Modulates Intestinal Glucose Absorption in Male Mice Fed a High-fat Diet

2022

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Hexokinase domain containing protein-1, or HKDC1, is a widely expressed hexokinase that is genetically associated with elevated 2-hour gestational blood glucose levels during an oral glucose tolerance test, suggesting a role for HKDC1 in postprandial glucose regulation during pregnancy. Our earlier studies utilizing mice containing global HKDC1 knockdown, as well as hepatic HKDC1 overexpression and knockout, indicated that HKDC1 is important for whole-body glucose homeostasis in aging and pregnancy, through modulation of glucose tolerance, peripheral tissue glucose utilization, and hepatic energy storage. However, our knowledge of the precise role(s) of HKDC1 in regulating postprandial glucose homeostasis under normal and diabetic conditions is lacking. Since the intestine is the main entry portal for dietary glucose, here we developed an intestine-specific HKDC1 knockout mouse model, HKDC1 Int-/-, to determine the in vivo role of intestinal HKDC1 in regulating glucose homeostasis. While no overt glycemic phenotype was observed, aged HKDC1 Int-/- mice fed a high fat diet exhibited an increased glucose excursion following an oral glucose load compared to mice expressing intestinal HKDC1. This finding resulted from glucose entry via the intestinal epithelium and is not due to differences in insulin levels, enterocyte glucose utilization, or reduction in peripheral skeletal muscle glucose uptake. Assessment of intestinal glucose transporters in high fat diet-fed HKDC1 Int-/- mice suggested increased apical GLUT2 expression in the fasting state. Taken together, our results indicate that intestinal HKDC1 contributes to the modulation of postprandial dietary glucose transport across the intestinal epithelium under conditions of enhanced metabolic stress, such as high fat diet.

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“…During euglycemic hyperinsulinemia (conditions that favor glycogen synthesis), the rate of muscle glucose uptake in mice ranges from 300 to 400 µmol/min/kg wet wt. Under these conditions, the amount of glucose diverted to glycogen synthesis ranges from ~ 1 to 5% of total glucose uptake, while glycolysis accounts for ≥ 95% of total uptake (Yang et al 2001 ; Cha et al 2011 ; Fujimoto et al 2021 ). In humans, muscle glucose uptake during euglycemic hyperinsulinemia (assuming for simplicity that all of leg weight is accounted for by muscle—assumption made by author) amounts to ~ 60 µmol/min/kg wet wt (basal value ~ 10) (DeFronzo et al 1985 ).…”

Section: Role Of Glycogen In Skeletal Musclementioning

confidence: 99%

A century of exercise physiology: key concepts in regulation of glycogen metabolism in skeletal muscle

Katz

2022

Eur J Appl Physiol

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Glycogen is a branched, glucose polymer and the storage form of glucose in cells. Glycogen has traditionally been viewed as a key substrate for muscle ATP production during conditions of high energy demand and considered to be limiting for work capacity and force generation under defined conditions. Glycogenolysis is catalyzed by phosphorylase, while glycogenesis is catalyzed by glycogen synthase. For many years, it was believed that a primer was required for de novo glycogen synthesis and the protein considered responsible for this process was ultimately discovered and named glycogenin. However, the subsequent observation of glycogen storage in the absence of functional glycogenin raises questions about the true role of the protein. In resting muscle, phosphorylase is generally considered to be present in two forms: non-phosphorylated and inactive (phosphorylase b) and phosphorylated and constitutively active (phosphorylase a). Initially, it was believed that activation of phosphorylase during intense muscle contraction was primarily accounted for by phosphorylation of phosphorylase b (activated by increases in AMP) to a, and that glycogen synthesis during recovery from exercise occurred solely through mechanisms controlled by glucose transport and glycogen synthase. However, it now appears that these views require modifications. Moreover, the traditional roles of glycogen in muscle function have been extended in recent years and in some instances, the original concepts have undergone revision. Thus, despite the extensive amount of knowledge accrued during the past 100 years, several critical questions remain regarding the regulation of glycogen metabolism and its role in living muscle.

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Disrupted glucose homeostasis and skeletal-muscle-specific glucose uptake in an exocyst knockout mouse model

Cited by 14 publications

References 41 publications

Transcriptome Analysis of Immune Receptor Activation and Energy Metabolism Reduction as the Underlying Mechanisms in Interleukin-6-Induced Skeletal Muscle Atrophy

Transcriptome Analysis of Immune Receptor Activation and Energy Metabolism Reduction as the Underlying Mechanisms in Interleukin-6-Induced Skeletal Muscle Atrophy

Enterocyte HKDC1 Modulates Intestinal Glucose Absorption in Male Mice Fed a High-fat Diet

A century of exercise physiology: key concepts in regulation of glycogen metabolism in skeletal muscle

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