biostudies-literatureKumar ABLRD VANIDDK NIH HHSNHLBI NIH HHSeadt6366https://www.ebi.ac.uk/biostudies/studies/S-EPMC12466849biostudies-literatureUnknown11(39)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 vivScience advancesLysosomal LRRC8 complex impacts lysosomal pH, morphology, and systemic glucose metabolism.PMC12466849R01 HL108379R01 DK127080R01 HL107594P30 DK020579R01 DK126068I01 BX004235K08 HL163469R01 DK106009I01 BX005981R01 HL168600I01 BX005065R01 DK115791I01 BX005072Liu HTranter JDMeyer GHong JAbel EDXie LHinton AFeng EXu HNorris AWZhao YDiwan AGrueter CESah RMikami RTAbraham NHenry KMHu MChadda RKumar ARawnsley DRfalseLysosomal LRRC8 complex impacts lysosomal pH, morphology, and systemic glucose metabolism.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 viv2025-01-01T00:00:00Z2025 Sep2026-06-03T21:36:35.26Z2026-05-02T03:07:39.791ZS-EPMC124668494100457110.1126/sciadv.adt6366