MON-647 - Lrrc2 Is A FOXO-Regulated Mediator of Skeletal Muscle Mitochondrial and Structural Adaptation in Diabetes

Background:
Skeletal muscle weakness and mitochondrial dysfunction are complications of diabetes. Reduced insulin action in diabetes activates FOXO transcription factors, which mediate detrimental mitochondrial changes in muscle. However, the FOXO-targets that coordinate muscle strength and mitochondrial adaptation remain incompletely understood. We identified leucine-rich repeat–containing protein 2 (Lrrc2) as a muscle-enriched FOXO target with mitochondrial localization and unknown function.

Objective:
To define the role of Lrrc2 in skeletal muscle adaptation to diabetic stress using integrated transcriptomic pathway analysis.

Methods:
Mitochondrial bioenergetics and RNA sequencing were performed in soleus from muscle-specific Lrrc2 knockout (KO) and littermate control (WT) mice under normoglycemia and 4 weeks after streptozotocin-induced diabetes (STZ). Permeabilized soleus fibers or isolated mitochondria from mixed quadriceps and gastrocnemius were used for respiration and ATP assays. Differential expression and pathway analyses were conducted using Advaita iPathwayGuide, including KEGG, Gene Ontology, upstream regulator, hallmark pathway, and meta-analyses across conditions.

Results:
Lrrc2 gene expression is induced in muscle 2 weeks after STZ treatment. Treadmill exercise tolerance was decreased in Lrrc2KO mice with and without diabetes, despite mild but significant hypertrophy of the soleus muscle. Mitochondrial respiration was unchanged in soleus fibers from all groups, but ATP production using Glutamate/Malate substrates was significantly decreased in Lrrc2KO STZ soleus fibers and isolated mitochondria. Lrrc2 loss resulted in 191 differentially expressed genes (DEGs, 1.5 fold, p< 0.1) under normoglycemia, with enrichment of protein digestion and absorption, muscle cytoskeleton, and ECM–receptor interaction KEGG pathways, each of which was primarily driven by an upregulation of collagen isoforms, indicating a role for Lrrc2 in repressing collagens. In contrast, Lrrc2 deficiency in diabetic muscle produced a larger transcriptional response (770 DEGs), characterized by activation of immune, phagocytic, and injury-associated pathways, alongside exaggerated muscle cytoskeleton KEGG pathways, again dominated by increased integrin and collagen gene expression. Within the Lrrc2 KO genotype, diabetes preferentially activated AMPK and PPAR signaling, fatty acid metabolism, and stress-response programs, consistent with impaired mitochondrial and metabolic flexibility.

Conclusion:
Lrrc2 is a FOXO-regulated effector that helps maintain mitochondrial ATP production and represses collagens in skeletal muscle. Loss of Lrrc2 shifts the diabetic muscle transcriptome toward injury-like and inflammatory states, providing a mechanistic link between FOXO activation, mitochondrial dysfunction, and muscle fibrosis in diabetes.

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