ArticleAmerican journal of physiology. Endocrinology and metabolism2013
Muscle-specific Pikfyve gene disruption causes glucose intolerance, insulin resistance, adiposity, and hyperinsulinemia but not muscle fiber-type switching.
Article in American journal of physiology. Endocrinology and metabolism, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 31 citations in OpenAlex.
- Relaxin-2: Shaping the Proteomic Landscape of Skeletal Muscle Physiology, Glucose Trafficking, and Mitochondrial Function in Rat.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Article
- PIKfyve preserves endolysosomal function in photoreceptors and RPE cells to maintain retinal integrity.Cell death & disease · 2026Article
- Lysosomal exocytosis by macrophages as a druggable mechanism for anti-inflammatory clearance of dead adipocytes in adipose tissue.Cell death & disease · 2025Article
- Identification of Anticancer Target Combinations to Treat Pancreatic Cancer and Its Associated Cachexia Using Constraint-Based Modeling.Molecules (Basel, Switzerland) · 2025Article
- Article
- Post-translational Modifications: The Signals at the Intersection of Exercise, Glucose Uptake, and Insulin Sensitivity.Endocrine reviews · 2022Review
- Roles of PIKfyve in multiple cellular pathways.Current opinion in cell biology · 2022Review
- Loss of hnRNP A1 in murine skeletal muscle exacerbates high-fat diet-induced onset of insulin resistance and hepatic steatosis.Journal of molecular cell biology · 2020Article
- PIKfyve Deficiency in Myeloid Cells Impairs Lysosomal Homeostasis in Macrophages and Promotes Systemic Inflammation in Mice.Molecular and cellular biology · 2019Article
- β-Actin shows limited mobility and is required only for supraphysiological insulin-stimulated glucose transport in young adult soleus muscle.American journal of physiology. Endocrinology and metabolism · 2018Article
- Rac1 muscle knockout exacerbates the detrimental effect of high-fat diet on insulin-stimulated muscle glucose uptake independently of Akt.The Journal of physiology · 2018Article
- Inhibition of PIKfyve prevents myocardial apoptosis and hypertrophy through activation of SIRT3 in obese mice.EMBO molecular medicine · 2017Article
- Exercise-stimulated glucose uptake - regulation and implications for glycaemic control.Nature reviews. Endocrinology · 2017Review
- Hepatic deletion of p110α and p85α results in insulin resistance despite sustained IRS1-associated phosphatidylinositol kinase activity.F1000Research · 2017Article
- Active vacuolar H+ ATPase and functional cycle of Rab5 are required for the vacuolation defect triggered by PtdIns(3,5)P2 loss under PIKfyve or Vps34 deficiency.American journal of physiology. Cell physiology · 2016Article
- Distinct Requirements for Vacuolar Protein Sorting 34 Downstream Effector Phosphatidylinositol 3-Phosphate 5-Kinase in Podocytes Versus Proximal Tubular Cells.Journal of the American Society of Nephrology : JASN · 2016Article
- Unexpected severe consequences of Pikfyve deletion by aP2- or Aq-promoter-driven Cre expression for glucose homeostasis and mammary gland development.Physiological reports · 2016Article
- Phosphoinositides: Key modulators of energy metabolism.Biochimica et biophysica acta · 2015Review
- Class III PI 3-kinase is the main source of PtdIns3P substrate and membrane recruitment signal for PIKfyve constitutive function in podocyte endomembrane homeostasis.Biochimica et biophysica acta · 2015Article
- The ML1Nx2 Phosphatidylinositol 3,5-Bisphosphate Probe Shows Poor Selectivity in Cells.PloS one · 2015Article
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
The evolutionarily conserved kinase PIKfyve that synthesizes PtdIns5P and PtdIns(3,5)P₂ has been implicated in insulin-regulated GLUT4 translocation/glucose entry in 3T3-L1 adipocytes. To decipher PIKfyve's role in muscle and systemic glucose metabolism, here we have developed a novel mouse model with Pikfyve gene disruption in striated muscle (MPIfKO). These mice exhibited systemic glucose intolerance and insulin resistance at an early age but had unaltered muscle mass or proportion of slow/fast-twitch muscle fibers. Insulin stimulation of in vivo or ex vivo glucose uptake and GLUT4 surface translocation was severely blunted in skeletal muscle. These changes were associated with premature attenuation of Akt phosphorylation in response to in vivo insulin, as tested in young mice. Starting at 10-11 wk of age, MPIfKO mice progressively accumulated greater body weight and fat mass. Despite increased adiposity, serum free fatty acid and triglyceride levels were normal until adulthood. Together with the undetectable lipid accumulation in liver, these data suggest that lipotoxicity and muscle fiber switching do not contribute to muscle insulin resistance in MPIfKO mice. Furthermore, the 80% increase in total fat mass resulted from increased fat cell size rather than altered fat cell number. The observed profound hyperinsulinemia combined with the documented increases in constitutive Akt activation, in vivo glucose uptake, and gene expression of key enzymes for fatty acid biosynthesis in MPIfKO fat tissue suggest that the latter is being sensitized for de novo lipid anabolism. Our data provide the first in vivo evidence that PIKfyve is essential for systemic glucose homeostasis and insulin-regulated glucose uptake/GLUT4 translocation in skeletal muscle.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.