Effect of treadmill exercise and bone marrow stromal cell engraftment on activation of BDNF-ERK-CREB signaling pathway in the crushed sciatic nerve

The effect of combined approach of exercise training and bone marrow stromal cell (BMSC) engraftment on activation of brain-derived neurotrophic factor (BDNF)-extracellular signal-regulated kinase 1 and 2 (ERK1/2)-cyclic adenosine monophosphate response element-binding protein (CREB) signaling pathway after sciatic nerve injury (SNI) was investigated. Sixty male Sprague-Dawley rats divided into the normal control, nonexercise (NEX), exercise training (EX), BMSC transplantation (TP), and exercise training+BMSC transplantation (EX+TP) groups 4 weeks after SCI. Exercise training was carried out on the treadmill device at 5–10 m/min for 20 min for 4 weeks. Single dose of 5× 106 harvested BMSC was injected into the injury area of the injured sciatic nerve. In order to evaluate induction levels of BDNF-ERK1/2-CREB signaling molecules in the whole cell and nuclear cell lysates of the injured sciatic nerve, we applied Western blot analysis. BDNF was significantly increased only in EX+TP compared to NEX, EX, and TP groups. Phosphoinositide-dependent kinase-1 was more increased in EX, TP, and EX+TP groups than NEX group, but EX+TP group showed the most upregulation of phosphorylated protein kinase B compared to other groups. In addition, in the whole cell lysate, phosphorylated ERK1/2, but not activating transcription factor-3 (ATF-3) and phosphorylated CREB, was significantly increased in TP and EX+TP groups. In the nuclear cell lysate, ATF-3 and phosphorylated CREB were strongly activated in EX+TP group compared to EX group. Regular exercise training combined with BMSC engraftment would seem to be more effective in controlling activation of regeneration-related signaling pathway after SNI.

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Effect of treadmill exercise combined with bone marrow stromal cell transplantation on atrophy-related signaling pathway in the denervated soleus muscle

Journal of Exercise Rehabilitation ◽

10.12965/jer.2142618.309 ◽

2021 ◽

Vol 17 (6) ◽

pp. 395-402

Author(s):

Yeong-Hyun Cho ◽

Tae-Beom Seo

Keyword(s):

Bone Marrow ◽

Sciatic Nerve ◽

Signaling Pathway ◽

Muscle Atrophy ◽

Soleus Muscle ◽

Stromal Cell ◽

Bone Marrow Stromal Cell ◽

Treadmill Exercise ◽

Marrow Stromal Cell ◽

Low Intensity

The purpose of this study was to investigate whether combination of low-intensity exercise with bone marrow stromal cell (BMSC) transplantation could regulate protein kinas B (Akt)- mammalian target of rapamycin (mTOR) and Wnt3a-β-catenin signaling pathways for prevention of soleus muscle atrophy after sciatic nerve injury (SNI). The experimental rats divided into 5 groups (n= 10): normal control group, SNI+sedentary group (SED), SNI+low-intensity treadmill exercise group (TEX), SNI+BMSC transplantation group (BMSC), SNI+TEX+BMSC transplantation group (TEX+BMSC). Sciatic nerve crush injury was applied into the middle of thigh twice for 1 min and 30 sec at interval. Low-intensity treadmill exercise was comprised of walking at a speed of 4 to 8 m/min for 30 min once a day. cultured BMSC at a density of 5× 106 in 50-μL phosphate-buffered saline was injected into the distal portion of the injured sciatic nerves. TEX+BMSC group dramatically upregulated expression levels of growth-associated protein-43 in the injured sciatic nerve at 2 weeks postinjury. Also, although Akt and mTOR signaling pathway significantly increased in TEX and BMSC groups than SED group, TEX+BMSC group showed more potent increment on this signaling in soleus muscle after SNI. Lastly, Wnt3a and the nuclear translocation of β-catenin and nuclear factor-kappa B in soleus were increased by SNI, but TEX+BMSC group significantly downregulated activity of this signaling pathway in the nuclear cell lysate of soleus muscle. Present findings provide new information that combination of low-intensity treadmill exercise might be effective therapeutic approach on restriction of soleus muscle atrophy after peripheral nerve injury.

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