Findings from recent studies by the Japan Aerospace Exploration Agency examining musculoskeletal atrophy in space and on Earth

The musculoskeletal system provides the body with correct posture, support, stability, and mobility. It is composed of the bones, muscles, cartilage, tendons, ligaments, joints, and other connective tissues. Without effective countermeasures, prolonged spaceflight under microgravity results in marked muscle and bone atrophy. The molecular and physiological mechanisms of this atrophy under unloaded conditions are gradually being revealed through spaceflight experiments conducted by the Japan Aerospace Exploration Agency using a variety of model organisms, including both aquatic and terrestrial animals, and terrestrial experiments conducted under the Living in Space project of the Japan Ministry of Education, Culture, Sports, Science, and Technology. Increasing our knowledge in this field will lead not only to an understanding of how to prevent muscle and bone atrophy in humans undergoing long-term space voyages but also to an understanding of countermeasures against age-related locomotive syndrome in the elderly

Rapid dissemination of alpha-synuclein seeds through neural circuits in an in-vivo prion-like seeding experiment

Abstract Accumulating evidence suggests that the lesions of Parkinson’s disease (PD) expand due to transneuronal spreading of fibrils composed of misfolded alpha-synuclein (a-syn), over the course of 5–10 years. However, the precise mechanisms and the processes underlying the spread of these fibril seeds have not been clarified in vivo. Here, we investigated the speed of a-syn transmission, which has not been a focus of previous a-syn transmission experiments, and whether a-syn pathologies spread in a neural circuit–dependent manner in the mouse brain. We injected a-syn preformed fibrils (PFFs), which are seeds for the propagation of a-syn deposits, either before or after callosotomy, to disconnect bilateral hemispheric connections. In mice that underwent callosotomy before the injection, the propagation of a-syn pathology to the contralateral hemisphere was clearly reduced. In contrast, mice that underwent callosotomy 24 h after a-syn PFFs injection showed a-syn pathology similar to that seen in mice without callosotomy. These results suggest that a-syn seeds are rapidly disseminated through neuronal circuits immediately after seed injection, in a prion-like seeding experiment in vivo, although it is believed that clinical a-syn pathologies take years to spread throughout the brain. In addition, we found that botulinum toxin B blocked the transsynaptic transmission of a-syn seeds by specifically inactivating the synaptic vesicle fusion machinery. This study offers a novel concept regarding a-syn propagation, based on the Braak hypothesis, and also cautions that experimental transmission systems may be examining a unique type of transmission, which differs from the clinical disease state

Nitric oxide-dependent modulation of the delayed rectifier K(+) current and the L-type Ca(2+) current by ginsenoside Re, an ingredient of Panax ginseng, in guinea-pig cardiomyocytes

1. Ginsenoside Re, a major ingredient of Panax ginseng, protects the heart against ischemia–reperfusion injury by shortening action potential duration (APD) and thereby prohibiting influx of excessive Ca(2+). Ginsenoside Re enhances the slowly activating component of the delayed rectifier K(+) current (I(Ks)) and suppresses the L-type Ca(2+) current (I(Ca,L)), which may account for APD shortening. 2. We used perforated configuration of patch-clamp technique to define the mechanism of enhancement of I(Ks) and suppression of I(Ca,L) by ginsenoside Re in guinea-pig ventricular myocytes. 3. S-Methylisothiourea (SMT, 1 μM), an inhibitor of nitric oxide (NO) synthase (NOS), and N-acetyl-L-cystein (LNAC, 1 mM), an NO scavenger, inhibited I(Ks) enhancement. Application of an NO donor, sodium nitroprusside (SNP, 1 mM), enhanced I(Ks) with a magnitude similar to that by a maximum dose (20 μM) of ginseonside Re, and subsequent application of ginsenoside Re failed to enhance I(Ks). Conversely, after I(Ks) had been enhanced by ginsenoside Re (20 μM), subsequently applied SNP failed to further enhance I(Ks). 4. An inhibitor of guanylate cyclase, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 10 μM), barely suppressed I(Ks) enhancement, while a thiol-alkylating reagent, N-ethylmaleimide (NEM, 0.5 mM), clearly suppressed it. A reducing reagent, di-thiothreitol (DTT, 5 mM), reversed both ginsenoside Re- and SNP-induced I(Ks) enhancement. 5. I(Ca,L) suppression by ginsenoside Re (3 μM) was abolished by SMT (1 μM) or LNAC (1 mM). NEM (0.5 mM) did not suppress I(Ca,L) inhibition and DTT (5 mM) did not reverse I(Ca,L) inhibition, whereas in the presence of ODQ (10 μM), ginsenoside Re (3 μM) failed to suppress I(Ca,L). 6. These results indicate that ginsenoside Re-induced I(Ks) enhancement and I(Ca,L) suppression involve NO actions. Direct S-nitrosylation of channel protein appears to be the main mechanism for I(Ks) enhancement, while a cGMP-dependent pathway is responsible for I(Ca,L) inhibition