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2516-P: In Vivo TurboID Mapping of Proteins Associated with a FoxO Target, LRRC2, in Skeletal Muscle Reveal Contractile–Mitochondrial Connections
Journal article   Peer reviewed

2516-P: In Vivo TurboID Mapping of Proteins Associated with a FoxO Target, LRRC2, in Skeletal Muscle Reveal Contractile–Mitochondrial Connections

Jack Friessen, Christie Penniman, Gourav Bhardwaj and Brian O'Neill
Diabetes (New York, N.Y.), Vol.75(Suppl 1), p.2516-P
06/01/2026
DOI: 10.2337/db26-2516-P

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Abstract

Introduction and Objective: FoxO-induced muscle weakness and mitochondrial dysfunction are pathologic consequences of diabetes, yet the molecular targets of FoxOs remain poorly defined. We discovered Leucine-rich repeat containing 2 (LRRC2) is a muscle enriched protein induced in diabetic muscle. Induction of LRRC2 by streptozotocin diabetes was prevented in muscle-specific FoxO knockout (KO) mice, indicating LRRC2 is a FoxO target. The objective of this study was to define LRRC2-protein interactions in muscle using proteomics. Methods: We generated muscle-specific LRRC2KO mice and show that mitochondrial ATP production was further impaired in diabetic LRRC2KO. To determine which proteins interact with LRRC2 we fused it to TurboID, an engineered ligase that labels proximal proteins with biotin. TurboID-LRRC2 was overexpressed in the tibialis anterior muscle via electroporation and TurboID-GFP was the contralateral control. Following biotin administration, muscles were harvested, biotinylated proteins were isolated on streptavidin-beads, and enriched proteins were identified by proteomics. Results: Proteomics showed 99 proteins were exclusively or significantly enriched in LRRC2-TurboID compared to GFP-TurboID. These proteins are involved in contractile structure, signaling, and mitochondrial proteins. The most enriched contractile proteins included Myl10, Tpm4, and Troponin T. Thirteen of the 99 enriched proteins are mitochondrially located, including Tomm20 and Tomm22 of the translocase of the outer membrane. Conclusion: These findings identify LRRC2 as a component of a mitochondrial network that may link insulin deficiency to structural and metabolic remodeling in diabetic muscle.
 Diabetes Proteomics Biotin Diabetes mellitus Electroporation Forkhead protein Mitochondria Muscle contraction Peptide mapping Protein interaction Proteins Skeletal muscle Streptavidin Streptozocin Tibialis anterior muscle Translocase Troponin Troponin T

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