PMID- 36385234 OWN - NLM STAT- MEDLINE DCOM- 20230124 LR - 20230124 IS - 1559-1182 (Electronic) IS - 0893-7648 (Linking) VI - 60 IP - 2 DP - 2023 Feb TI - Moderate-Intensity Treadmill Exercise Promotes mTOR-Dependent Motor Cortical Neurotrophic Factor Expression and Functional Recovery in a Murine Model of Crush Spinal Cord Injury (SCI). PG - 960-978 LID - 10.1007/s12035-022-03117-6 [doi] AB - Treadmill exercise is widely considered an effective strategy for restoration of skilled motor function after spinal cord injury (SCI). However, the specific exercise intensity that optimizes recovery and the underlying mechanistic basis of this recovery remain unclear. To that end, we sought to investigate the effect of different treadmill exercise intensities on cortical mTOR activity, a key regulator of functional recovery following CNS trauma, in an animal model of C5 crush spinal cord injury (SCI). Following injury, animals were subjected to treadmill exercise for 4 consecutive weeks at three different intensities (low intensity [LEI]; moderate intensity [MEI]; and high intensity [HEI]). Motor function recovery was assessed by horizontal ladder test, cylinder rearing test, and electrophysiology, while neurotrophic factors and cortical mechanistic target of rapamycin (mTOR) pathway-related proteins were assessed by Western blotting. The activation of the cortical mTOR pathway and axonal sprouting was evaluated by immunofluorescence and the changes of plasticity in motor cortex neurons were assessed by Golgi staining. In keeping with previous studies, we found that 4 weeks of treadmill training resulted in improved skilled motor function, enhanced nerve conduction capability, increased neuroplasticity, and axonal sprouting. Importantly, we also demonstrated that when compared with the LEI group, MEI and HEI groups demonstrated elevated expression of brain-derived neurotrophic factor (BDNF), insulin-like growth factor 1 (IGF-1), phosphorylated ribosomal S6 protein (p-S6), and protein kinase B (p-Akt), consistent with an intensity-dependent activation of the mTOR pathway and neurotrophic factor expression in the motor cortex. We also observed impaired exercise endurance and higher mortality during training in the HEI group than in the LEI and MEI groups. Collectively, our findings suggest that treadmill exercise following SCI is an effective means of promoting recovery and highlight the importance of the cortical mTOR pathway and neurotrophic factors as mediators of this effect. Importantly, our findings also demonstrate that excessive exercise can be detrimental, suggesting that moderation may be the optimal strategy. These findings provide an important foundation for further investigation of treadmill training as a modality for recovery following spinal cord injury and of the underlying mechanisms. CI - (c) 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature. FAU - Zhan, Zuxiong AU - Zhan Z AD - Department of Rehabilitation Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China. FAU - Pan, Lu AU - Pan L AD - Department of Rehabilitation Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China. FAU - Zhu, Ying AU - Zhu Y AD - Department of Rehabilitation Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China. FAU - Wang, Yunhang AU - Wang Y AD - Department of Rehabilitation Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China. FAU - Zhao, Qin AU - Zhao Q AD - Department of Rehabilitation Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China. FAU - Liu, Yuan AU - Liu Y AD - State Key Laboratory of Trauma, Burns and Combined Injury, Department of Special War Wound, Daping Hospital, Army Medical University, Chongqing, 400042, China. FAU - Li, Sen AU - Li S AD - State Key Laboratory of Trauma, Burns and Combined Injury, Department of Special War Wound, Daping Hospital, Army Medical University, Chongqing, 400042, China. FAU - Wang, Haiyan AU - Wang H AD - State Key Laboratory of Trauma, Burns and Combined Injury, Department of Special War Wound, Daping Hospital, Army Medical University, Chongqing, 400042, China. FAU - Yang, Ce AU - Yang C AD - State Key Laboratory of Trauma, Burns and Combined Injury, Department of Special War Wound, Daping Hospital, Army Medical University, Chongqing, 400042, China. FAU - Yu, Lehua AU - Yu L AD - Department of Rehabilitation Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China. FAU - Yin, Ying AU - Yin Y AD - Department of Rehabilitation Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China. 300735@cqmu.edu.cn. FAU - Tan, Botao AU - Tan B AUID- ORCID: 0000-0001-8513-3416 AD - Department of Rehabilitation Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China. 303518@cqmu.edu.cn. LA - eng GR - 81702221/National Natural Science Foundation of China/ GR - 82002377/National Natural Science Foundation of China/ GR - cstc2020jcyj-msxm0161/Natural Science Foundation Project of Chongqing, Chongqing Science and Technology Commission/ GR - cstc2019jcyj-msxmX0195/Natural Science Foundation Project of Chongqing, Chongqing Science and Technology Commission/ GR - cstc2018jcyjAX0180/Natural Science Foundation Project of Chongqing, Chongqing Science and Technology Commission/ PT - Journal Article DEP - 20221117 PL - United States TA - Mol Neurobiol JT - Molecular neurobiology JID - 8900963 RN - 0 (Brain-Derived Neurotrophic Factor) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.1.1 (mTOR protein, mouse) SB - IM MH - Animals MH - Mice MH - Brain-Derived Neurotrophic Factor/metabolism MH - Disease Models, Animal MH - Motor Neurons/metabolism MH - Recovery of Function/physiology MH - Spinal Cord/metabolism MH - *Spinal Cord Injuries/metabolism MH - TOR Serine-Threonine Kinases/metabolism OTO - NOTNLM OT - BDNF OT - Neuroplasticity OT - Neurotrophic factors OT - Rehabilitation OT - Spinal cord injury (SCI) OT - Treadmill training OT - mTOR EDAT- 2022/11/18 06:00 MHDA- 2023/01/21 06:00 CRDT- 2022/11/17 10:42 PHST- 2022/06/10 00:00 [received] PHST- 2022/11/01 00:00 [accepted] PHST- 2022/11/18 06:00 [pubmed] PHST- 2023/01/21 06:00 [medline] PHST- 2022/11/17 10:42 [entrez] AID - 10.1007/s12035-022-03117-6 [pii] AID - 10.1007/s12035-022-03117-6 [doi] PST - ppublish SO - Mol Neurobiol. 2023 Feb;60(2):960-978. doi: 10.1007/s12035-022-03117-6. Epub 2022 Nov 17.