The purpose of the present study was to investigate how the effects of high-fat diet feeding on the skeletal muscle persisted during aging using mice. Post-weaned male mice were fed a high-fat diet between 1- and 3-mo-old followed by return to supply a normal diet until 13-mo-old. Monthly physical tests demonstrated that age-related glucose intolerance that was generally developed after 10-mo-old in the control mice was significantly improved in mice fed a high-fat diet. Interestingly, mRNA expressions of Pdk4, Ucp3, and Zmynd17 were up-regulated by high-fat feeding and persisted in the tibialis anterior muscle until 13-mo-old. At Pdk4 and Ucp3 loci, enhanced distributions of active histone modifications were noted in the high-fat-fed mice at 13-mo-old. In contrast, age-related accumulation of histone variant H3.3 at these loci was suppressed. These results indicated that epigenetic modifications caused by early nutrition mediated the changes in skeletal muscle gene expression during aging.
Hindlimb suspension of rats induces induces fiber atrophy and type shift of muscle fibers. In contrast, there is no change in the cell size or oxidative enzyme activity of spinal motoneurons innervating muscle fibers. Growth-related increases in the cell size of muscle fibers and their spinal motoneurons are inhibited by hindlimb suspension. Exposure to microgravity induces atrophy of fibers (especially slow-twitch fibers) and shift of fibers from slow- to fast-twitch type in skeletal muscles (especially slow, anti-gravity muscles). In addition, a decrease in the oxidative enzyme activity of spinal motoneurons innervating slow-twitch fibers and of sensory neurons in the dorsal root ganglion is observed following exposure to microgravity. It is concluded that neuromuscular activities are important for maintaining metabolism and function of neuromuscular systems at an early postnatal development and that gravity effects both efferent and afferent neural pathways.
We screened serum samples from patients with various hematological disorders and healthy individuals for the presence of adult T-cell leukemia/lymphoma associated antigen (anti-ATLA) antibodies. These antibodies were detected not only in all patients with ATL but frequently in those diagnosed as T-cell malignant lymphoma or T-cell chronic lymphocytic leukemia; the positivity rate of anti-ATLA antibody was lower in B- and null-cell-type lymphoma, B-cell chronic lymphocytic leukemia, and multiple myeloma. Patients with aplastic anemia or acute leukemia who had received frequent and massive blood transfusions also possessed anti-ATLA antibodies. About 5.5% of the healthy individuals over 40 years of age in the endemic area (Kumamoto) were carriers. The rate of positivity gradually increased with age, and was higher in females than in males. In addition, the peripheral blood mono-nuclear cells and/or lymph node cells from patients with various hematological disorders, including ATL, were examined. The presence of human T-cell leukemia/lymphoma virus type I (HTLV-I) proviral DNA was confirmed in all patients with ATL and in some with T-cell-type malignant lymphomas. However, in HTLV-I carriers or other patients with hematological disorders without ATL, proviral DNA was not detected. In endemic areas, detection of proviral DNA is essential for the classification and diagnosis of T-cell malignancies.
Exercise training causes epigenetic changes in skeletal muscle, although it is unclear how resistance exercise (RE) affects histone modifications. The present study was carried out to investigate the effects of acute RE and RE training on gene expression profiles and histone modifications in human skeletal muscle. Healthy male adults were assigned to acute RE (n = 9, age = 20.5±4.3yr, BMI = 28.0±6.8kg/m2) or RE training (n = 21, age = 23.7±2.5yr, BMI = 24.2±2.7kg/m2) groups. Biopsy samples were obtained from the vastus lateralis muscle before and three hours after a single bout of acute RE, or 3-days after 10 weeks of RE training. RNA sequencing analysis revealed that 153 genes with GO terms including muscle development, stress response, metabolism, cell death, and transcription factor were significantly up-regulated (+291% vs. pre-acute RE) upon acute RE. Expressions of these genes were also greater (+9.6% vs. pre-RE training, p<0.05) in RE trained subjects. Significant up-regulation of acetylated histone 3 (H3) (+235%) and H3 mono-methylated at lysine 4 (+290%) and tri-methylated at lysine 27 (+849%), whereas down-regulation of H3.3 variant (−39%) distributions relative to total H3 were observed at transcriptionally activated loci after acute RE compared to pre-acute RE levels. Interestingly, the distribution of acetylated H3 was found to be up-regulated as compared to the level of total H3 after RE training (+40%, p<0.05). These results indicate that a single bout of RE drastically alters both gene expressions and histone modifications in human skeletal muscle. It is also suggested that enhanced histone acetylation is closely related to up-regulation of gene expressions after RE training.
Neural circuits between lesions are one mechanism through which local inflammation spreads to remote positions. Here, we show the inflammatory signal on one side of the joint is spread to the other side via sensory neuron–interneuron crosstalk, with ATP at the core. Surgical ablation or pharmacological inhibition of this neural pathway prevented inflammation development on the other side. Mechanistic analysis showed that ATP serves as both a neurotransmitter and an inflammation enhancer, thus acting as an intermediary between the local inflammation and neural pathway that induces inflammation on the other side. These results suggest blockade of this neural pathway, which is named the remote inflammation gateway reflex, may have therapeutic value for inflammatory diseases, particularly those, such as rheumatoid arthritis, in which inflammation spreads to remote positions.
Effects of gravitational loading or unloading on the gain of the characteristics in soleus muscle fibers were studied in rats. The tail suspension was performed in newborn rats from postnatal day 4 to month 3, and the reloading was allowed for 3 mo in some rats. Single expression of type I myosin heavy chain (MHC) was observed in approximately 82% of fibers in 3-mo-old controls, but the fibers expressing multiple MHC isoforms were noted in the unloaded rats. Although 97% of fibers in 3-mo-old controls had a single neuromuscular junction at the central region of fiber, fibers with multiple nerve endplates were seen in the unloaded group. Faster contraction speed and lower maximal tension development, even after normalization with fiber size, were observed in the unloaded pure type I MHC fibers. These parameters generally returned to the age-matched control levels after reloading. It was suggested that antigravity-related tonic activity plays an important role in the gain of single neural innervation and of slow contractile properties and phenotype in soleus muscle fibers.
The present study was carried out to investigate the effects of anemia on the protein expression in rat thalamus. The powdered diet containing 100 or 3 ppm iron was fed in rats with the age of 3‐week. After 20 weeks of supplementation, blood and thalamus including hypothalamus were sampled from both groups. The hematocrit and hemoglobin content were 44 and 15 g/dl in the 100 ppm group, respectively. However, they were less (17 and 4 g/dl) in the 3 ppm group. The two‐dimensional electrophoresis was performed using the homogenate of thalamus. As the result, 73 kDa heat shock protein (HSP73) was found in the spot which expression level was greater in 3 ppm group. Further, western blot was performed to check the quantitative expression level. Although the level of total HSP73 was greater (+89%) in the 3 ppm group, no differences were seen if they were compared among spots with the different isoelectric points. The iron deficiency‐induced anemia may cause some changes in thalamus function via HSP73 expression. This study was supported by Grant‐in‐Aid for Scientific Research S (19100009) and Exploratory Research (20650104) from JSPS, and Young Scientists B (21700656) from MEXT.
Long-term running training causes epigenetic changes in the skeletal muscles. Here we tested the effects of the total amount or duration of running training on the distribution of histones in the rat plantaris muscle. Post-weaned young rats were assigned to 3 different training groups: Run-1, 30 min/day running exercise for 8 wk using an animal treadmill at 24 m/min; Run-2, 15 min/day for 8 wk; and Run-3, 60 min/day for 4 wk. Citrate synthase activity was not significantly changed by running training, although the slight increase was observed in Run-3. Genes that were previously defined as showing the typical responses to running training were targeted to measure the distribution of histones using chromatin immunoprecipitation. The distribution of acetylated histone 3 was elevated in Run-2 and Run-3, but not in Run-1. Incorporation of H3.3 into the nucleosome was stimulated in Run-1, whereas H3.3 distribution was unchanged in Run-2 or downregulated in Run-3. Significant downregulation of H3.3 expression was also detected in Run-3. We further checked the responses of the target genes during acute running. Target genes were transcriptionally activated and histone acetylation was stimulated at the loci in response to acute running. These results suggested that the exchange of the histone component to H3.3 was stimulated by running training, inhibiting the accumulation of acetylated histones in Run-1. Additionally, it was further suggested that the enhanced daily amount of running caused changes in the H3.3 expression, affecting the rate of the histone exchange in Run-3. NEW & NOTEWORTHY Chromatin remodeling in the skeletal muscle is a potent mechanism preventing disuse atrophy in later life that can be acquired via long-term exercise training. Here we demonstrated in rats that daily exercise amount is a key factor in the development of epigenetic changes in the skeletal muscle. To acquire a health benefit, our research suggests the importance of considering the time endurance for daily exercise bouts.
