Physical Weight Loading Induces Expression of Tryptophan Hydroxylase 2 in the Brain Stem

Abstract

Sustaining brain serotonin is essential in mental health. Physical activities can attenuate mental problems by enhancing serotonin signaling. However, such activity is not always possible in disabled individuals or patients with dementia. Knee loading, a form of physical activity, has been found to mimic effects of voluntary exercise. Focusing on serotonergic signaling, we addressed a question: Does local mechanical loading to the skeleton elevate expression of tryptophan hydroxylase 2 (tph2) that is a rate-limiting enzyme for brain serotonin? A 5 min knee loading was applied to mice using 1 N force at 5 Hz for 1,500 cycles. A 5-min treadmill running was used as an exercise (positive) control, and a 90-min tail suspension was used as a stress (negative) control. Expression of tph2 was determined 30 min – 2 h in three brain regions ––frontal cortex (FC), ventromedial hypothalamus (VMH), and brain stem (BS). We demonstrated for the first time that knee loading and treadmill exercise upregulated the mRNA level of tph2 in the BS, while tail suspension downregulated it. The protein level of tph2 in the BS was also upregulated by knee loading and downregulated by tail suspension. Furthermore, the downregulation of tph2 mRNA by tail suspension can be partially suppressed by pre-application of knee loading. The expression of tph2 in the FC and VMH was not significantly altered with knee loading. In this study we provided evidence that peripheral mechanical loading can activate central tph2 expression, suggesting that physical cues may mediate tph2-cathalyzed serotonergic signaling in the brain.

Unraveling the Molecular Determinants of Manual Therapy: An Approach to Integrative Therapeutics for the Treatment of Fibromyalgia and Chronic Fatigue Syndrome/Myalgic Encephalomyelitis

“…The group led by Yokota, on another side, used a commercial knee electro-mechanical loading system (ElectroForce 3100, Bose Corporation, Eden Praire, MN, USA) which applies lateral loads to the knee to induce anabolic responses in the skeleton [ 60 , 61 ] to study the effects of this treatment in rat brains [ 42 ]. The rationale behind their hypothesis derived from the observation that physical activities, regularly involving application of a mechanical load on the skeleton, seem to have a stimulatory role in pain control, neural regeneration and synthesis of neurotransmitters [ 43 , 62 , 63 ].…”

“…The rationale behind their hypothesis derived from the observation that physical activities, regularly involving application of a mechanical load on the skeleton, seem to have a stimulatory role in pain control, neural regeneration and synthesis of neurotransmitters [ 43 , 62 , 63 ]. The authors show that by using RT-qPCR, western-blot and immunohistochemistry analysis, that knee loading of 1 N at 5Hz for 1500 cycles and a 5 min treadmill running (positive control) upregulated messenger RNA (mRNA) levels of tryptophan hydroxylase 2 ( Tph 2) in the raphe nuclei of brain stem, the site of serotonin synthesis in the brain, in reference to sham load and 90 min tail suspension (stressed negative control) [ 42 ]. In addition, these authors showed that the mRNAs encoding two transcription factors of the Tph 2 gene ( Sim 1 and Pet 1) were significantly upregulated by this knee-loading treatment as well [ 43 ].…”

Unraveling molecular determinants of manual therapy: an approach to integrative therapeutics for the treatment of fibromyalgia and CFS/ME

“…The group led by Yokota, on another side, used a commercial knee electro-mechanical loading system (ElectroForce 3100, Bose Corporation, Eden Praire, MN) which applies lateral loads to the knee to induce anabolic responses in the skeleton [55,56] to study the effects of this treatment in rat brains [57]. The rationale behind their hypothesis derived from the observation that physical activities, regularly involving application of a mechanical load on the skeleton, seem to have a stimulatory role in pain control, neural regeneration and synthesis of neurotransmitters [58][59][60].…”

“…The rationale behind their hypothesis derived from the observation that physical activities, regularly involving application of a mechanical load on the skeleton, seem to have a stimulatory role in pain control, neural regeneration and synthesis of neurotransmitters [58][59][60]. The authors show by using RT-qPCR, western-blot and immunohistochemistry analysis, that knee loading of 1 N at 5Hz for 1500 cycles and a 5 minute treadmill running (positive control) upregulated mRNA levels of tryptophan hydroxylase 2 (tph2) in the raphe nuclei of brain stem, the site of serotonin synthesis in the brain, in reference to sham load and 90 minute tail suspension (stressed negative control) [57]. In addition, these authors showed that the mRNAs encoding two transcription factors of the Tph2 gene (Sim1 and Pet1) were significantly upregulated by this knee-loading treatment as well [58].…”

Mechanical stimulations can inhibit local and remote tumor progression by downregulating WISP1

“…9 It is also reported that knee loading can activate neuronal signaling and elevate the serotonin level in the brain. 10 We have previously shown that ankle loading, the other form of joint loading modality, ameliorated tumor-driven bone loss by inhibiting the nuclear factor of activated T-cells cytoplasmic 1 (NFATc1)-driven bone resorption in the loaded tibia. 11 However, little is known about loading effects on systemic metabolites or tumorigenesis that is not directly linked to bone homeostasis.…”