2. Academic Validation
  3. Leptin promotes tendon stem/progenitor cell senescence through the AKT-mTOR signaling pathway

Leptin promotes tendon stem/progenitor cell senescence through the AKT-mTOR signaling pathway

  • Exp Cell Res. 2024 Oct 1;442(2):114274. doi: 10.1016/j.yexcr.2024.114274.
Changbin Lei 1,  Yanmei Li 2,  Jiafeng Chen 3,  Daibang Nie 3,  Xin Song 3,  Cece Lei 3,  Yiqin Zhou 4,  Wang Wang 5,  Jiuyi Sun 6
Affiliations

Affiliations

  • 1 Department of Orthopedics, Affiliated Hospital of Xiangnan University, Chenzhou, 423000, China.
  • 2 Department of Medical Technology and Health Management, Chongqing Nursing Vocational College, Chongqing, 400010, China; Department of Immunology, School of Basic Medical Sciences, Chongqing Medical University, Chongqing, 400010, China.
  • 3 Department of Immunology, School of Basic Medical Sciences, Chongqing Medical University, Chongqing, 400010, China; Chongqing Key Laboratory of Tumor Immune Regulation and Immune Intervention, Chongqing Medical University, Chongqing, 400010, China.
  • 4 Department of Orthopedics, Shanghai Changzheng Hospital, Naval Medical University, Shanghai, 200000, China.
  • 5 Department of Immunology, School of Basic Medical Sciences, Chongqing Medical University, Chongqing, 400010, China; Chongqing Key Laboratory of Tumor Immune Regulation and Immune Intervention, Chongqing Medical University, Chongqing, 400010, China. Electronic address: wwang@cqmu.edu.cn.
  • 6 Department of Orthropedics, Navy Medical Center of PLA, Naval Medical University, Shanghai, 200000, China. Electronic address: sunjiuyi@smmu.edu.cn.
PMID: 39393753 DOI: 10.1016/j.yexcr.2024.114274
Abstract

Dysregulated adipokine production is an influencing factor for the homeostatic imbalance of tendons. High levels of serum Leptin may be a potential link between increasing adiposity and tendinopathy, while the detailed mechanistic explanation was not well-defined. In this study, we investigated the regulatory role of Leptin in the tendon stem/progenitor cells (TSPCs) and the molecular mechanism within, and determined the effect of high levels of Leptin on tendon recovery. We demonstrated that Leptin reduced the viability of isolated rat TSPCs in a dose-dependent way, accompanied with increased transdifferentiation and altered gene expression of a series of extracellular matrix (ECM) enzymatic modulators. Also, we found that Leptin could dose-dependently promote TSPCs senescence, while exhibiting limited effect in apoptotic or autophagic induction. Mechanistic study evidenced that Leptin treatment increased the Akt/mTOR signaling activity and elevated the expression of Leptin receptor (LEPR) in TSPCs, without marked change in MAPK or STAT5 activation. Further, we confirmed that rapamycin treatment, but not Akt inhibition, effectively reduced the leptin-promoted TSPCs senescence. In a rat model with Achilles wounding, exposure to Leptin profoundly delayed tendon healing, which was effectively rescued with rapamycin treatment. Our results suggested that Leptin could cause intrinsic cellular deficits in TSPCs and impede tendon repair through the Akt/mTOR signaling pathway. These findings evidenced for an important role of elevated Leptin levels in the care of tendinopathy and tendon tears.

Keywords

Leptin; Senescence; TSPC; Tendon; mTOR.

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