Year: 2025
Type: article
Abstract: The lysosome integrates anabolic signaling and nutrient sensing to regulate intracellular growth pathways. The leucine-rich repeat-containing 8 (LRRC8) channel complex forms a lysosomal anion channel and regulates PI3K-AKT-mTOR signaling, skeletal muscle differentiation, growth, and systemic glucose metabolism. Here, we define the endogenous LRRC8 subunits localized to a subset of lysosomes in differentiated myotubes. We show that LRRC8A affects leucine-stimulated mTOR; lysosome size; number; pH; expression of lysosomal proteins LAMP2, P62, and LC3B; and lysosomal function. Mutating an LRRC8A lysosomal targeting dileucine motif sequence (LRRC8A-L706A;L707A) in myotubes recapitulates the abnormal AKT signaling and altered lysosomal morphology and pH observed in LRRC8A knockout cells. In vivo, LRRC8A-L706A;L707A knock-in mice exhibit increased adiposity, impaired glucose tolerance and insulin resistance associated with reduced skeletal muscle PI3K-AKT-mTOR signaling, glucose uptake, and impaired incorporation of glucose into glycogen. These data reveal a lysosomal LRRC8-mediated metabolic signaling function regulating lysosomal function, systemic glucose homeostasis, and insulin sensitivity.
Source: Science Advances
Authors: Ashutosh Kumar, Yonghui Zhao, Litao Xie, Rahul Chadda, John D. Tranter, Ryan T. Mikami, Nihil Abraham, Juan Hong, Ethan Feng, David R. Rawnsley, Haiyan Liu, Kayla M. Henry, Gretchen Meyer, Meiqin Hu, Haoxing Xu, Antentor Hinton, Chad E. Grueter, E. Dale Abel, Andrew W. Norris, Abhinav Diwan, Rajan Sah
Language: English
Subfield: Physiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,500
Funders: U.S. Department of Veterans Affairs, Washington University in St. Louis, Children's Discovery Institute, National Institutes of Health, Center for Cellular Imaging, Washington University, National Heart, Lung, and Blood Institute, National Institute of Diabetes and Digestive and Kidney Diseases
Awards: G187799067, Insulin Resistance and Myocardial Autophagy, G2087982354, G2337220457, G261815350, G2630370920, G2841219562, G3672917242, SWELL1-LRRC8 mediated regulation of skeletal muscle function and metabolism, G5578448820, G5746972746, Splanchno-Hormonal Mechanisms of Cystic Fibrosis Related Diabetes, G6278108438, G63402963, G7635470215, G9000025623, G9000141885, G9000153645, Targeting Lysosome Function in Lipid Overload Cardiomyopathy
OpenAlex ID: W4414537937