Takanori Kokubun

Exercise enhances cognitive function and neurotrophin expression in the hippocampus accompanied by changes in epigenetic programming in senescence-accelerated mice

Aerobic exercise is known to increase expression of neurotrophins, particularly brain-derived neurotrophic factor (BDNF), in the hippocampus and to improve cognitive function. Exercise exerts neuroprotective effects in the hippocampus by inducing epigenetic changes, which play crucial roles in aging and neurodegenerative diseases. Specifically, the activity levels of histone acetyltransferases (HATs) and histone deacetylases (HDACs) regulate histone acetylation and modulate gene transcription. The objective of the present study was to assess the interactive effects of exercise and aging on cognitive function, expression of neurotrophins (BDNF and neurotrophin-4) and their receptors (tyrosine receptor kinase B and p75), and epigenetic regulations, including the activity of HATs and HADCs in the hippocampus. We used the senescence-accelerated mouse (SAM) model, specifically 13-month-old SAM resistant 1(SAMR1) and SAM prone 1 (SAMP1) lines. Mice were distributed into four groups based on accelerated senescence and exercise status. Mice in the exercise groups exercised on a treadmill for approximately 60min a day, 5days a week. Aerobic exercise for 4 weeks improved cognitive function, accompanied by an increase in BDNF expression and a decrease in p75 transcription in both SAMR1 and SAMP1. In addition, the exercise regimen activated both HAT and HDAC in the hippocampus. Therefore, the present study reveals that despite accelerated senescence, long-term exercise improved cognitive function, upregulated the expression of BDNF, and downregulated p75, a receptor involved in apoptotic signaling. Furthermore, long-term exercise enhanced activity of both HAT and HDAC, which may contribute to the transcriptional regulation underlying the improvement of cognitive function.

Controlling Abnormal Joint Movement Inhibits Response of Osteophyte Formation

Objective Osteoarthritis (OA) is induced by accumulated mechanical stress to joints; however, little has been reported regarding the cause among detailed mechanical stress on cartilage degeneration. This study investigated the influence of the control of abnormal joint movement induced by anterior cruciate ligament (ACL) injury in the articular cartilage. Design The animals were divided into 3 experimental groups: CAJM group (n = 22: controlling abnormal joint movement), ACL-T group (n = 22: ACL transection or knee anterior instability increased), and INTACT group (n = 12: no surgery). After 2 and 4 weeks, the knees were harvested for digital microscopic observation, soft X-ray analysis, histological analysis, and synovial membrane molecular evaluation. Results The 4-week OARSI scores showed that cartilage degeneration was significantly inhibited in the CAJM group as compared with the ACL-T group (P < 0.001). At 4 weeks, the osteophyte formation had also significantly increased in the ACL-T group (P < 0.001). These results reflected the microscopic scoring and soft X-ray analysis findings at 4 weeks. Real-time synovial membrane polymerase chain reaction analysis for evaluation of the osteophyte formation–associated factors showed that the mRNA expression of BMP-2 and VEGF in the ACL-T group had significantly increased after 2 weeks. Conclusions Typically, abnormal mechanical stress induces osteophyte formation; however, our results demonstrated that CAJM group inhibited osteophyte formation. Therefore, controlling abnormal joint movement may be a beneficial precautionary measure for OA progression in the future.

Muscle synergies underlying sit-to-stand tasks in elderly people and their relationship with kinetic characteristics

BACKGROUND Physiological evidence suggests that the nervous system controls motion by using a low-dimensional synergy organization for muscle activation. Because the muscle activation produces joint torques, kinetic changes accompanying aging can be related to changes in muscle synergies. OBJECTIVES We explored the effects of aging on muscle synergies underlying sit-to-stand tasks, and examined their relationships with kinetic characteristics. METHODS Four younger and three older adults performed the sit-to-stand task at two speeds. Subsequently, we extracted the muscle synergies used to perform these tasks. Hierarchical cluster analysis was used to classify these synergies. We also calculated kinetic variables to compare the groups. RESULTS Three independent muscle synergies generally appeared in each subject. The spatial structure of these synergies was similar across age groups. The change in motion speed affected only the temporal structure of these synergies. However, subject-specific muscle synergies and kinetic variables existed. CONCLUSIONS Our results suggest common muscle synergies underlying the sit-to-stand task in both young and elderly adults. People may actively change only the temporal structure of each muscle synergy. The precise subject-specific structuring of each muscle synergy may incorporate knowledge of the musculoskeletal kinetics.

Restoring knee joint kinematics after anterior cruciate ligament injury might inhibit synovial membrane inflammation

We developed a novel controlled abnormal joint movement (CAJM) model that controls instability after traditional anterior cruciate ligament transection (ACL-T). We evaluated whether joint instability damping suppresses synovial inflammation in osteoarthritis patients using our new CAJM rat model. We found that joint instability in rats differed between the ACL-T and CAJM models. Joint instability might contribute to synovitis and inhibit osteoarthritis.

Effects of Controlling Abnormal Joint Movement on Expression of MMP13 and TIMP-1 in Osteoarthritis:

Objective Abnormal joint movement is associated with osteoarthritis (OA). Previous studies using the controlling abnormal joint movement (CAJM) model of OA reported delayed cartilage degeneration; however, none of them focused on gait performance and the localization of matrix metalloproteinase 13 (MMP13) and tissue inhibitor of metalloproteinase-1 (TIMP-1) in chondrocytes. Therefore, we aimed to investigate the effect of controlling abnormal joint movement on gait performance and the localization of MMP13 and TIMP-1, using kinematic and histological analyses. Design Rats were assigned to 2 groups: anterior cruciate ligament transection (ACL-T) group and CAJM group (n = 5/group); contralateral hind limbs of ACL-T rats were designated as intact. After 1, 2, and 4 weeks, step length was analyzed, and after 2, 4, and 8 weeks, Safranin O-Fast Green staining and immunohistochemical staining for MMP13 and TIMP-1 were performed. Results Step length did not differ significantly between the groups. However, degeneration of articular cartilage was higher in the ACL-T group than in the intact group (P < 0.05). There was no significant difference in the CAJM group at all time points. Immunohistochemical analysis of the MMP13/TIMP-1 relationship revealed a significant increase in the expression ratio of MMP13 after 4 weeks in the ACL-T group compared to the CAJM group (P < 0.05). Conclusions Controlling abnormal joint movement may reduce mechanical stress owing to kinematic elements of small articulation including joint instability and delayed cartilage degeneration, despite the lack of kinematic change in step length.

Key Determinants of Anterior Cruciate Ligament Spontaneous Healing

Anterior cruciate ligament (ACL) injuries are known to have very low rates of spontaneous healing. There have been several studies since the mid-1960s concerning the approaches to accelerate spontaneous healing of ACL injuries. Recent studies have identified similarities in the healing response of ACL and other extra-articular ligaments, in terms of their cellular response and vascularity. Research has demonstrated that mechanical stress has an important influence on the biological response of tissue healing. Novel treatment approaches may exploit the role of mechanical loads on the regulation of gene expression in achieving spontaneous healing of injured ACL. This article reviews the determinants of the ACL healing response and their relationship to mechanical stress and spontaneous healing, and explores novel concepts that are emerging in the management of ACL injuries.