Our results showed that VAT provided relaxation effects to elderly nursing home residents and promoted passive aerobic exercise, consequently improving symptoms of depression and improving sleep patterns [7
The results of previous VAT studies using PC12 m3 cells exposed to vibratory stimuli at frequencies of 10–200 Hz for 30 min followed by NGF treatment showed that vibrations of 20–100 Hz (low frequency) enhanced neurite outgrowth. In the present study, the frequency of neurite outgrowth induced by 40-Hz (low frequency) vibrations was approximately three-fold greater than that induced by NGF alone. Activation of the p38 MAPK (mitogen-activated protein kinase) pathway plays an important role in neuronal differentiation of PC12 m3 cells. Therefore, we examined whether the ability of a low-frequency vibratory stimulus to induce neurite outgrowth of PC12 m3 cells is a reflection of its effect on p38 MAPK activity [5
]. The results showed that vibratory stimuli induced neurite outgrowth via the p38 MAPK signaling pathway in PC12 m3 cells.
In studies on intracellular transduction pathways of aerobic exercise using mouse muscle cells, Akimoto proposed a pathway where MKK3/MKK6 in MAPKK is activated by aerobic exercise, leading to downstream p38MAPK activation and eventual biosynthesis of mitochondria [18
]. Moreover, Falempin et al. suggested that tendon vibration (120 Hz) of murine soleus muscle can be used as a paradigm to counteract the atrophic process observed after hind-limb unloading [19
]. In addition, Blumenthal reported that aerobic exercise is effective for alleviating depression in the elderly, with an effect comparable to that of antidepressant drugs [20
]. In consideration of these findings, mitigation of depression due to VAT for elderly NH residents seems to be enhanced by vibro-tactile stimuli due to passive aerobic exercise. Still, the p38MARK signaling pathway has been reported to have protective effects on cardiac muscle [21
Vascular endothelial cell growth factor (VEGF) induces endothelial cell proliferation and movement, remodeling of the extracellular matrix, the formation of capillary tubules, and vascular leakage [22
]. Moreover, VEGF plays a crucial role in the development of the cardiovascular system and in promoting angiogenesis that is associated with physiological and pathological processes [23
]. VEGF is an endothelial cell-specific mitogen that promotes numerous other phenomena that are necessary for angiogenesis [24
Mitogen-activated protein kinase (MAPK) is important in the induction of endothelial cell proliferation that is induced by VEGF [25
]. VEGF promotes the phosphorylation and activation of the cyclic AMP-responsive element binding protein (CREB) by activating p38 MAPK/mitogen-and stress-activated protein kinase-1 (MSK-1) signaling pathways that are downstream of the kinase insert domain receptor (KDR; vascular endothelial cell growth factor receptor-2) [26
]. Because CREB is a transcription factor that plays an important role in promoting cellular proliferation and adaptive responses, a mechanism has been defined by which VEGF/KDR may allow endothelial cells to respond to changes in their environment through alterations in their gene expression [24
]. These findings indicate that by mediating cellular responses to VEGF, CREB, through its activation of p38 MAPK/ MSK-1 signaling pathways, is likely to play an important role in endothelial cell function and blood development.
In the present study, p38 MAPK was activated by vibratory stimulation at 7 Hz for 10 min and promoted neurite outgrowth by PC12m3 cells of approximately 3-fold greater than that induced by NGF alone. Furthermore, neurite outgrowth induction by low-frequency vibration was inhibited by a specific p38 MAPK inhibitor, SB203580, in the presence of NGF. A recent study demonstrated that p38 MAPK participated in preserving neurite growth cones during neurite outgrowth and in regulating cellular differentiation and survival. These results suggest that p38 MAPK was not involved in neurite outgrowth that was inducted by7 Hz vibratory stimulation.
Moreover, we detected an activated cyclic-AMP responsive element (CRE)-binding protein (CREB) expression in PC12m3 cells after vibratory stimulation at 7 Hz. CREB is a transcription factor that is the target of a various signaling pathways that mediate cell responses to extracellular stimuli, including proliferation, differentiation, and adaptive responses. p38 MAPK can promote CREB binding to CRE. Our results suggested that p38 MAPK may induce neurite outgrowth by PC12m3 cells via a CREB signaling pathway. This indicates that p38MAPK may induce neurite outgrowth via a CREB signaling pathway after low-frequency whole body vibration.
Another recent study suggested that mechanical stimulation by whole body vibration increased shear stress at the walls of blood vessels, which resulted in increased blood flow velocity after vibration was terminated and promoted muscle deoxygenation [28
]. Increased shear stress in capillaries in skeletal muscle can initiate capillary growth by producing a disturbance in the luminal side of the basement membrane [30
]. It appears likely that shear stress can induce angiogenesis [31
All of these findings indicate that whole body vibration induced CREB expression by activating a p38 MAPK signaling pathway. This signaling pathway is likely to play an important role in endothelial cell function and blood development.