Blockade of the Succinate-SUCNR1 Metabolic Axis Helps Restore Mitochondrial Homeostasis and Prevents Structural Failure in Overuse-Induced Rotator Cuff Tendinopathy in a Mouse Model.

BACKGROUND: Rotator cuff repair failures are primarily driven by intrinsic tissue degeneration. While mitochondrial dysfunction is implicated in this cascade, the specific metabolic signals driving structural tendon failure remain poorly defined. The succinate-SUCNR1 axis may function as a critical metabolic checkpoint in this process.

HYPOTHESIS: The authors hypothesized that the succinate-SUCNR1 axis is clinically hyperactivated in rotator cuff tears (RCTs), and that targeted blockade of this axis would mitigate overuse-induced tissue degeneration and preserve ultimate biomechanical integrity.

METHODS: Human supraspinatus specimens (10 RCTs, 10 controls) were analyzed for succinate levels, SUCNR1 expression, and histological severity. A murine treadmill overuse model was established in wild-type (WT) and Sucnr1-deficient (Sucnr1-/-) mice (21 per group) to evaluate histological degeneration, pathological neovascularization, and biomechanical properties (ultimate failure load and stiffness). Mechanistically, senescent human tendon stem cells (hTSCs) (n = 6) were treated with a selective SUCNR1 antagonist (Compound 20) to evaluate mitochondrial bioenergetic rescue via seahorse analysis.

RESULTS: In RCT specimens, tissue degeneration strongly correlated with succinate accumulation and SUCNR1 upregulation (Pearson r = 0.81; P < .001). In vivo, Sucnr1 deficiency protected mice from overuse-induced tendinopathy, significantly suppressing inflammatory infiltration and aberrant neovascularization while maintaining collagen architecture. Sucnr1 ablation prevented the significant loss of tendon stiffness and ultimate failure load observed in the WT overuse group (P < .01). In vitro, SUCNR1 antagonism restored mitochondrial respiration, preserved cristae ultrastructure, and attenuated the stress-induced senescent phenotype in hTSCs.

CONCLUSION: The succinate-SUCNR1 axis is a potent driver of structural failure. Targeting this axis may help restore mitochondrial homeostasis and break the "inflamm-aging" cycle, potentially reducing retear rates after rotator cuff repair.

CLINICAL RELEVANCE: Pharmacological blockade of SUCNR1 represents a promising, biology-preserving strategy to improve intrinsic tendon quality. By helping restore mitochondrial homeostasis and halting the degenerative cascade, targeting this axis may reduce structural failure rates after rotator cuff repair.

STUDY DESIGN: Controlled laboratory study.