FNIP1 abrogation promotes functional revascularization of ischemic skeletal muscle by driving macrophage recruitment

Zongchao Sun, Likun Yang, Abdukahar Kiram, Jing Yang, Zhuangzhuang Yang, Liwei Xiao, Yujing Yin, Jing Liu, Yan Mao, Danxia Zhou, Hao Yu, Zheng Zhou, Dengqiu Xu, Yuhuan Jia, Chenyun Ding, Qiqi Guo, Hongwei Wang, Yan Li, Li Wang, Tingting Fu (), Shijun Hu () and Zhenji Gan ()
Additional contact information
Zongchao Sun: Medical School of Nanjing University, Nanjing University
Likun Yang: Medical School of Nanjing University, Nanjing University
Abdukahar Kiram: Medical School of Nanjing University, Nanjing University
Jing Yang: Medical School of Nanjing University, Nanjing University
Zhuangzhuang Yang: Soochow University
Liwei Xiao: Medical School of Nanjing University, Nanjing University
Yujing Yin: Medical School of Nanjing University, Nanjing University
Jing Liu: Medical School of Nanjing University, Nanjing University
Yan Mao: Medical School of Nanjing University, Nanjing University
Danxia Zhou: Medical School of Nanjing University, Nanjing University
Hao Yu: Medical School of Nanjing University, Nanjing University
Zheng Zhou: Medical School of Nanjing University, Nanjing University
Dengqiu Xu: Medical School of Nanjing University, Nanjing University
Yuhuan Jia: Medical School of Nanjing University, Nanjing University
Chenyun Ding: Medical School of Nanjing University, Nanjing University
Qiqi Guo: Medical School of Nanjing University, Nanjing University
Hongwei Wang: Medical School of Nanjing University
Yan Li: Jiangnan University
Li Wang: Jiangnan University
Tingting Fu: Medical School of Nanjing University, Nanjing University
Shijun Hu: Soochow University
Zhenji Gan: Medical School of Nanjing University, Nanjing University

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract Ischaemia of the heart and limbs attributable to compromised blood supply is a major cause of mortality and morbidity. The mechanisms of functional angiogenesis remain poorly understood, however. Here we show that FNIP1 plays a critical role in controlling skeletal muscle functional angiogenesis, a process pivotal for muscle revascularization during ischemia. Muscle FNIP1 expression is down-regulated by exercise. Genetic overexpression of FNIP1 in myofiber causes limited angiogenesis in mice, whereas its myofiber-specific ablation markedly promotes the formation of functional blood vessels. Interestingly, the increased muscle angiogenesis is independent of AMPK but due to enhanced macrophage recruitment in FNIP1-depleted muscles. Mechanistically, myofiber FNIP1 deficiency induces PGC-1α to activate chemokine gene transcription, thereby driving macrophage recruitment and muscle angiogenesis program. Furthermore, in a mouse hindlimb ischemia model of peripheral artery disease, the loss of myofiber FNIP1 significantly improved the recovery of blood flow. Thus, these results reveal a pivotal role of FNIP1 as a negative regulator of functional angiogenesis in muscle, offering insight into potential therapeutic strategies for ischemic diseases.

Date: 2023
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DOI: 10.1038/s41467-023-42690-9

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