This study has to do with the brain but it has to do with loading effects and is done by Hiroki Yokota one of the LSJL scientists. The study shows that in some cases LSJL may upregulate Sim1 which does have an effect on height. However, it’s usually Sim1 deficiency that increases height(but also obesity).
The intent of the study seems to be establishing that Lateral Synovial Joint Loading can be used on sedentary individuals who can’t do other forms of exercise can do this exercise to help prevent various mental problems. Since LSJL decreases Nerve Growth Factor-Beta(which is involved in pain perception) and increases Serotonin it could induce a feeling of euphoria or well-being. I have noted this myself when performing LSJL. Treadmill exercise was compared as well which has bounds of anecdotal evidence of not being able to increase height so tph2 is not likely able to increase height as an adult.
If LSJL upregulates genes that are negative for growth such as Sim1 and NGF-Beta(even if these genes are not very directly related to the processes key to growth plate chondrogenesis), maybe this could indicate that other genes related to growth are regulated in the wrong direction at this load level too. Although the LSJL lengthening study did take place at similar loads. It could indicate that the loads used were not sufficient enough. And the loads need to be such that NGF-Beta is upregulated and Sim1 is downregulated however these two genes could just be tangentially related to longitudinal bone growth and their regulation is independent of LSJL’s lengthening effects.
Physical weight loading induces expression of tryptophan hydroxylase 2 in the brain stem.
“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{applied laterally so this is an LSJL study} 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.”
“C57/BL/6 male and female mice, 6 to 8 weeks of age”
“The loaded tissue [under LSJL] is significantly softer and more energy dissipative than bone matrix in the femur and tibia.”
“In response to a 1 N force applied at 5 Hz to the mouse knee, the phase shift angle between the force and resulting displacement was found to be 18.1°. The energy loss per cycle was calculated to be 0.201 mJ, and the Young’s modulus of the knee joint was determined as 166 MPa”
“Cyclic compression was applied to the mouse left knee using an electro-mechanical loading device (ElectroForce® 3100, Bose Corporation, Eden Prairie, MN).”<-Electroforce is available for sale here. The other versions ie. 3200 are even more expensive but can apply heavier loads. I’m not sure how viable it is to apply this to the knee and there’s no price so it’s probably incredibly expensive.
“Knee loading and treadmill exercise induced significant upregulation of type I collagen mRNA in the femur and tibia, as well as type II collagen mRNA in cartilage. Furthermore, unloading through tail suspension for 90 min led to significant reduction of type II collagen in cartilage. However, unloading did not present significant change in type I collagen mRNA as compared to the untreated controls. Although not significant, knee loading at 1 N showed a decreasing trend of NGFß in the femur and cartilage as compared to the control”
In fact Treadmill exercise had a stronger impact on type II collagen than LSJL did. I emailed Hiroki Yokota and he says he believed the removed all the cartilage from the bone in this study including growth plate cartilage. It’s possible that this removal of cartilage also removed other regions of the bone that would normally express type II collagen. Ideally we would want to see expression of type II collagen in other regions of bone other than the growth plate cartilage as that would be a clear sign of ectopic chondrocyte differentiation.
In this study, the mRNA at an unclear timepoint post loading in contrast to 1 hour following loading as done in the LSJL gene expression study. It’s possible that Col2a1 was upregulated 1 hour following loading but returned to normal at some period post loading. There are some pathways that are upregulated 1 hour post loading. For example, plasma discharge treatment only elevates some factors one hour post treatment. And enhanced phosphorylation of JNK can return to baseline at one hour in some cases. Also, the LSJL gene expression study involved microarray data and this involve RT-PCR.
” Among two known upstream transcription factors, mRNA expression of Sim1 in the BS of mice treated with knee loading was significantly increased as compared to that of the sham loaded controls.”<-Does Sim1 have any effect on height?
According to Rare variants in single-minded 1 (SIM1) are associated with severe obesity., Sim1 mainly relates to energy homeostasis.
“Final height in SIM1-deficient adults was not increased. The lack of accelerated linear growth in patients with SIM1 mutations contrasts with the phenotype of [one] patient and the phenotype of Sim1 heterozygous mice. This difference may be explained by partial versus complete loss of SIM1 activity. ” Height was less than versus control obese subjects. Height was increased in MC4R deficient subjects.
“accelerated linear growth and increased final height seen in MC4R deficiency”
Here’s the study dealing with the patient mentioned:
Profound obesity associated with a balanced translocation that disrupts the SIM1 gene.
“We have studied a unique girl with early-onset obesity and a de novo balanced translocation between chromosomes 1p22.1 and 6q16.2. Her weight gain is most likely due to excessive food intake, since measured energy expenditure was normal. We cloned and sequenced both translocation breakpoints. The translocation does not appear to affect any transcription unit on 1p, but it disrupts the SIM1 gene on 6q. SIM1 encodes a human homolog of Drosophila Sim (Single-minded), a transcription factor involved in midline neurogenesis, and is a prototypical member of the bHLH-PAS (basic helix-loop-helix + period, aryl hydrocarbon receptor, Single-minded) gene family. Our subject’s trans- location separates the 5′ promoter region and bHLH domain from the 3′ PAS and putative transcriptional regulation domains. The transcriptional targets of SIM1 are not known. Mouse Sim1 is expressed in the developing kidney and central nervous system, and is essential for formation of the supraoptic and paraventricular (PVN) nuclei of the hypothalamus. Previous neuroanatomical and pharmacological studies have implicated the PVN in the regulation of body weight: PVN neurons express the melanocortin 4 receptor and appear to be physiological targets of alpha-melanocyte-stimulating hormone, which inhibits food intake. We hypothesize that haploinsufficiency of SIM1, possibly acting upstream or downstream of the melanocortin 4 receptor in the PVN, is responsible for severe obesity in our subject.”
“The proband (SW116) was referred to a pediatric geneticist at age 18 months because of excessive growth.”
“We identified a mutation in the SIM1 gene in a girl with profound obesity and increased linear growth.”<-they suspect the mutation was SIM1 haploinsufficiency.
Back to the LSJL study:
“Knee loading led to increases of transcription factor, Sim 1 and Pet 1 mRNA but not REST/NRSF in the BS”
” Other target genes of Sim1, lhx8 and RGS4 did not show significant alteration with knee loading applied in the present study. However, we did find the upregulation of lhx8 and RGS4 mRNA in the BS (hindbrain) as compared to the VMH (midbrain)”
“load-driven upregulation of tph2 mRNA persisted at least 2 h”
“In this study, we showed the effect of peripheral mechanical loading on the brain. The observed remote effect can potentially be mediated through central projecting stimulation and neuronal signaling with neurotrophins. For instance, NGFß is a member of the neurotrophins that is involved in pain sensation and survival of neuron in the brain. Alternatively, loading can be sensed through alterations in the level of hormones and growth factors in the serum. Through signaling molecules in blood circulation, gene expression in the BS might be regulated. Knee loading induces direct loading effects, including formation of new bone, stimulation of fracture healing, prevention of cartilage degeneration, and suppression of pain in the knee. Knee loading can modulate brain serotonin level through tph2 in the BS.”<-Here’s the study that shows that LSJL decreases NGF-Beta. Serotonin may have an effect on height via LRP5. Although the exact effect of LRP5 on height is unclear.