Myokines in home-based functional electrical stimulation-induced recovery of skeletal muscle in elderly and permanent denervation

Neuromuscular disorders, disuse, inadequate nutrition, metabolic diseases, cancer and aging produce muscle atrophy and this implies that there are different types of molecular triggers and signaling pathways for muscle wasting. Exercise and muscle contractions may counteract muscle atrophy by releasing a group of peptides, termed myokines, to protect the functionality and to enhance the exercise capacity of skeletal muscle. In this review, we are looking at the role of myokines in the recovery of permanent denervated and elderly skeletal muscle tissue. Since sub-clinical denervation events contribute to both atrophy and the decreased contractile speed of aged muscle, we saw a parallel to spinal cord injury and decided to look at both groups together. The muscle from lifelong active seniors has more muscle bulk and more slow fiber-type groupings than those of sedentary seniors, demonstrating that physical activity maintains slow motoneurons that reinnervate the transiently denervated muscle fibers. Furthermore, we summarized the evidence that muscle degeneration occur with irreversible Conus and Cauda Equina syndrome, a spinal cord injury in which the human leg muscles may be permanently disconnected from the peripheral nervous system. In these patients, suffering with an estreme case of muscle disuse, a complete loss of muscle fibers occurs within five to ten years after injury. Their recovered tetanic contractility, induced by home-based Functional Electrical Stimulation, can restore the muscle size and function in compliant Spinal Cord Injury patients, allowing them to perform electrical stimulation-supported stand-up training. Myokines are produced and released by muscle fibers under contraction and exert both local and systemic effects. Changes in patterns of myokine secretion, particularly of IGF-1 isoforms, occur in long-term Spinal Cord Injury persons and also in very aged people. Their modulation in Spinal Cord Injury and late aging are also key factors of home-based Functional Electrical Stimulation - mediated muscle recovery. Thus, Functional Electrical Stimulation should be prescribed in critical care units and nursing facilities, if persons are unable or reluctant to exercise. This will result in less frequent hospitalizations and a reduced burden on patients' families and public health services

Signals from the Niche: Insights into the Role of IGF-1 and IL-6 in Modulating Skeletal Muscle Fibrosis

Abstract Muscle regeneration, characterized by the activation and proliferation of satellite cells and other precursors, is accompanied by an inflammatory response and the remodeling of the extracellular matrix (ECM), necessary to remove cellular debris and to mechanically support newly generated myofibers and activated satellite cells. Muscle repair can be considered concluded when the tissue architecture, vascularization, and innervation have been restored. Alterations in these connected mechanisms can impair muscle regeneration, leading to the replacement of functional muscle tissue with a fibrotic scar. In the present review, we will discuss the cellular mediators of fibrosis and how the altered expression and secretion of soluble mediators, such as IL-6 and IGF-1, can modulate regulatory networks involved in the altered regeneration and fibrosis during aging and diseases

『法華文化研究』の電子情報化について（『法華文化研究』第33号）

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道徳授業における発問と道徳的価値の関連性について ―基本発問・中心発問と関連価値・中心価値の関連性を中心に―

text紀要論文 / Departmental Bulletin Paperdepartmental bulletin pape

Metabolic changes associated with muscle expression of SOD1G93A

Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disorder, classified into sporadic or familial forms and characterized by motor neurons death, muscle atrophy, weakness, and paralysis. Among the familial cases of ALS, approximately 20% are caused by dominant mutations in the gene coding for superoxide dismutase (SOD1) protein. Of note, mutant SOD1 toxicity is not necessarily limited to the central nervous system. ALS is indeed a multi-systemic and multifactorial disease that affects whole body physiology and induces severe metabolic changes in several tissues, including skeletal muscle. Nevertheless, whether alterations in the plasticity, heterogeneity, and metabolism of muscle fibers are the result of motor neuron degeneration or alternatively occur independently of it remain to be elucidated. To address this issue, we made use of a mouse model (MLC/SOD1G93A) that overexpresses the SOD1 mutant gene selectively in skeletal muscle. We found an alteration in the metabolic properties of skeletal muscle characterized by alteration in fiber type composition and metabolism. Indeed, we observed an alteration of muscle glucose metabolism associated with the induction of Phosphofructokinases and Pyruvate dehydrogenase kinase 4 expression. The upregulation of Pyruvate dehydrogenase kinase 4 led to the inhibition of Pyruvate conversion into Acetyl-CoA. Moreover, we demonstrated that the MLC/SOD1G93Atransgene was associated with an increase of lipid catabolism and with the inhibition of fat deposition inside muscle fibers. All together these data demonstrate that muscle expression of the SOD1G93Agene induces metabolic changes, along with a preferential use of lipid energy fuel by muscle fibers. We provided evidences that muscle metabolic alterations occurred before disease symptoms and independently of motor neuron degeneration, indicating that skeletal muscle is likely an important therapeutic target in ALS

Taurine Administration Counteracts Aging-Associated Impingement of Skeletal Muscle Regeneration by Reducing Inflammation and Oxidative Stress

Abstract: Sarcopenia, which occurs during aging, is characterized by the gradual loss of skeletal muscle mass and function, resulting in a functional decline in physical abilities. Several factors contribute to the onset of sarcopenia, including reduced regenerative capacity, chronic low-grade inflammation, mitochondrial dysfunction, and increased oxidative stress, leading to the activation of catabolic pathways. Physical activity and adequate protein intake are considered effective strategies able to reduce the incidence and severity of sarcopenia by exerting beneficial effects in improving the muscular anabolic response during aging. Taurine is a non-essential amino acid that is highly expressed in mammalian tissues and, particularly, in skeletal muscle where it is involved in the regulation of biological processes and where it acts as an antioxidant and anti-inflammatory factor. Here, we evaluated whether taurine administration in old mice counteracts the physiopathological effects of aging in skeletal muscle. We showed that, in injured muscle, taurine enhances the regenerative process by downregulating the inflammatory response and preserving muscle fiber integrity. Moreover, taurine attenuates ROS production in aged muscles by maintaining a proper cellular redox balance, acting as an antioxidant molecule. Although further studies are needed to better elucidate the molecular mechanisms responsible for the beneficial effect of taurine on skeletal muscle homeostasis, these data demonstrate that taurine administration ameliorates the microenvironment allowing an efficient regenerative process and attenuation of the catabolic pathways related to the onset of sarcopenia

Impact of Vitamin E‐Coated Membrane Hemodiafilter on Serum Albumin Redox State in the Acute Kidney Injury Pig Hemodialysis Model

Background Several studies have evaluated the biocompatibility of dialysis membranes. The use of vitamin E-coated membranes has been reported multilaterally in in vitro and clinical studies. Nevertheless, the effect of vitamin E-coated membranes on the redox state of serum albumin, which forms the largest fraction of reactive sulfhydryl groups, has not been reported. Methods Hemodiafiltration (HDF) with and without a vitamin E-coated hemodiafilter (V-RATM group and ABHTM groups, respectively) was performed in an acute kidney injury pig model to determine whether changes in the serum albumin, the oxidized albumin (OxiALB), and the reduced albumin (RedALB) levels differ between the two groups. Results Analyses were conducted 22–24 times in the V-RATM group and 16–18 times in the ABHTM group, excluding missing data. The serum albumin levels decreased in both groups after nephrectomy; however, the decrease observed in the V-RATM group was significantly lesser than that in the ABHTM group. RedALB levels were significantly higher in the V-RATM group; in contrast, OxiALB levels did not differ between the two groups. A significant positive correlation was observed between the serum albumin and RedALB levels. Conclusions The present study demonstrated that HDF performed using a vitamin E-coated hemodiafilter effectively minimized the reduction in serum albumin and RedALB levels compared to the vitamin E-non-coated hemodiafilter in an acute kidney injury pig model.Citation: Shouichi Fujimoto, Masahide Koremoto, Shushi Yamamoto, Hiroshi Umeno, Yusuke Sano, Toshihiro Tsuruda, Impact of Vitamin E‐Coated Membrane Hemodiafilter on Serum Albumin Redox State in the Acute Kidney Injury Pig Hemodialysis Model, Artificial Organs, 2025-03-19, https://doi.org/10.1111/aor.1498

Levetiracetam enhances the temozolomide effect on glioblastoma stem cell proliferation and apoptosis

Abstract BACKGROUND: Glioblastoma multiforme (GBM) is a highly aggressive brain tumor in which cancer cells with stem cell-like features, called cancer stem cells (CSCs), were identified. Two CSC populations have been previously identified in GBM, one derived from the GBM area called enhanced lesion (GCSCs) and the other one from the brain area adjacent to the tumor margin (PCSCs) that greatly differ in their growth properties and tumor-initiating ability. To date the most effective chemotherapy to treat GBM is represented by alkylating agents such as temozolomide (TMZ), whose activity can be regulated by histone deacetylases (HDACs) inhibitors through the modulation of O6-methylguanine-DNA methyltransferase (MGMT) expression. Levetiracetam (LEV), a relatively new antiepileptic drug, modulates HDAC levels ultimately silencing MGMT, thus increasing TMZ effectiveness. However, an improvement in the therapeutic efficacy of TMZ is needed. METHODS: Cell proliferation was investigated by BrdU cell proliferation assay and by Western Blot analysis of PCNA expression. Apoptosis was evaluated by Western Blot and Immunofluorescence analysis of the cleaved Caspase-3 expression. MGMT and HDAC4 expression was analyzed by Western Blotting and Immunofluorescence. Statistical analysis was performed using the Student's t test and Mann-Whitney test. RESULTS: Here we evaluated the effect of TMZ on the proliferation rate of the IDH-wildtype GCSCs and PCSCs derived from six patients, in comparison with the effects of other drugs such as etoposide, irinotecan and carboplatin. Our results demonstrated that TMZ was less effective compared to the other agents; hence, we verified the possibility to increase the effect of TMZ by combining it with LEV. Here we show that LEV enhances the effect of TMZ on GCSCs proliferation (being less effective on PCSCs) by decreasing MGMT expression, promoting HDAC4 nuclear translocation and activating apoptotic pathway. CONCLUSIONS: Although further studies are needed to determine the exact mechanism by which LEV makes GBM stem cells more sensitive to TMZ, these results suggest that the clinical therapeutic efficacy of TMZ in GBM might be enhanced by the combined treatment with LEV

若手教員と語る -教育現場の現在と課題-

Articledepartmental bulletin pape

Analysis of Mechanisms for Increased Blood Pressure Variability in Rats Continuously Infused with Angiotensin II

Objective. We reported that rats infused with angiotensin II (Ang II) are not only a model of hypertension but also of augmented 24 h blood pressure variability (BPV). In this study, we examined the mechanisms for Ang II-induced BPV, focusing on BP, heart rate (HR), baroreceptor reflex sensitivity (BRS), and medial area of the aortic arch. Methods. Nine-week-old male Wistar rats were infused with subcutaneous 5.2 μg/kg/h Ang II with or without oral administration with 30 mg/kg/day azelnidipine for 14 days. BP and HR were recorded every 15 min under an unrestrained condition by a radiotelemetry system, while BPV was evaluated by standard deviation of BP. BRS was quantified by a sequence analysis, and medial thickness of the aortic arch was measured by microscopic examination. Results. BPV increased at days 7 and 14 following continuous infusion of Ang II. Before the infusion, a positive correlation was found between BP and HR, but it became negative at day 7 and then weakened or disappeared at day 14. BRS was slightly impaired at day 7 and significantly lowered at day 14, a phenomenon accompanied by thickened medial area of the aortic arch in Ang II-infused rats. Those Ang II-induced alterations were all significantly attenuated by azelnidipine. Conclusions. The present findings suggest sequential changes in the mechanisms behind augmented BPV in rats continuously infused with Ang II over 14 days.Citation: Jiang Danfeng, Matsuzaki Minami, Kawagoe Yukiko, Kitamura Kazuo, Tsuruda Toshihiro, Kaikita Koichi, Asada Yujiro, Kato Johji. Analysis of Mechanisms for Increased Blood Pressure Variability in Rats Continuously Infused with Angiotensin II. Journal of the Renin-Angiotensin-Aldosterone System. 2023; 2023:4201342. doi: 10.1155/2023/4201342