Biology subjects

Nikawa, T.

Publications and source records attributed to Nikawa, T..

4 recordsLinked to original sources

bioRxiv2023

The reciprocal regulation between mitochondrial-associated membranes and Notch signaling in skeletal muscle atrophy

Skeletal muscle atrophy and the inhibition of muscle regeneration are known to occur as a natural consequence of aging, yet the underlying mechanisms that lead to these processes in atrophic myofibers remain largely unclear. Our research has revealed that the maintenance of proper mitochondrial-associated endoplasmic reticulum membranes (MAM) is vital for preventing skeletal muscle atrophy in microgravity environments. We discovered that the deletion of the mitochondrial fusion protein Mitofusin2 (MFN2), which serves as a tether for MAM, in human iPS cells or the reduction of MAM in differentiated myotubes caused by microgravity interfered with myogenic differentiation process and an increased susceptibility to muscle atrophy, as well as the activation of the Notch signaling pathway. The atrophic phenotype of differentiated myotubes in microgravity and the regenerative capacity of Mfn2-deficient muscle stem cells in dystrophic mice were both ameliorated by treatment with the gamma-secretase inhibitor DAPT. Our findings demonstrate how the orchestration of mitochondrial morphology in differentiated myotubes and regenerating muscle stem cells plays a crucial role in regulating Notch signaling through the interaction of MAM. digestThis study investigated the link between Mfn2 and Notch signaling in skeletal muscle atrophy. We used a microgravity system to induce muscle atrophy and found that the loss of Mfn2 leads to decreased numbers of MAM and activation of Notch signaling and that treating MFN2-deficient human iPS cells with a gamma-secretase inhibitor DAPT improved their mitochondrial morphology and function. Additionally, Mfn2-deficient muscle stem cells in mice have a lower capacity to regenerate dystrophic muscles and DAPT treatment improves the regeneration of these cells. The study suggests that targeting the Notch signaling pathway with a gamma-secretase inhibitor could be a therapeutic option for skeletal muscle atrophy caused by defects in Mfn2.

developmental biology↗

bioRxiv2021

All-trans retinoic acid induces GADD34 gene expression via transcriptional regulation by Six1-TLE3 and post-transcriptional regulation by p38-TTP in skeletal muscle

All-trans retinoic acid (ATRA) increases the sensitivity to unfolded protein response (UPR) in differentiating leukemic blasts. The downstream transcriptional factors of PERK, a major arm of UPR, regulates muscle differentiation. However, the role of growth arrest and DNA damage-inducible protein 34 (GADD34), one of the downstream factors of PERK, and the effects of ATRA on GADD34 expression in muscle remain unclear. In this study, we identified ATRA increased the GADD34 expression independent of the PERK signal in the gastrocnemius muscle of mice. ATRA up-regulated GADD34 expression through the transcriptional activation of it via inhibiting the interaction of homeobox Six1 and transcription co-repressor TLE3 with the MEF3-binding site on the GADD34 gene promoter in myoblasts. ATRA also inhibited the interaction of TTP, which induces mRNA degradation, with AU-rich element on GADD34 mRNA via p38 MAPK, resulting in the instability of GADD34 mRNA. Overexpressed GADD34 in myoblasts changes the type of myosin heavy chain in myotubes. These results suggest ATRA increases GADD34 expression via transcriptional and post-transcriptional regulation in myoblasts, which changes muscle fiber type in myotubes.

biochemistry↗

bioRxiv2020

Cystal structure of inhibitor-bound human MSPL/TMPRSS13 that can activate high pathogenic avian influenza

Infection of certain influenza viruses is triggered when its hemagglutinin (HA) is cleaved by host cell proteases such as proprotein convertases and type II transmembrane serine proteases (TTSP). HA with a monobasic motif is cleaved by trypsin-like proteases, including TMPRSS2 and HAT, while the multibasic motif found in high pathogenicity avian influenza HA is cleaved by furin, PC5/6, or MSPL. MSPL belongs to the TMPRSS family and preferentially cleaves [R/K]-K-K-R{downarrow} sequences. Here, we solved the crystal structure of the extracellular region of human MSPL in complex with an irreversible substrate-analog inhibitor. The structure revealed three domains clustered around the C-terminal -helix of the SPD. The inhibitor structure and its putative model show that the P1-Arg inserts into the S1 pocket, whereas the P2-Lys and P4-Arg interacts with the Asp/Glu-rich 99-loop that is unique to MSPL. Based on the structure of MSPL, we also constructed a homology model of TMPRSS2, which is essential for the activation of the SARS-CoV-2 spike protein and infection. The model may provide the structural insight for the drug development for COVID-19.

biophysics↗

bioRxiv2019

Identification of a fatty acid-sensitive interaction between mitochondrial uncoupling protein 3 and enoyl-CoA hydratase 1 in skeletal muscle

Skeletal muscle mitochondrial fatty acid (FA) overload in response to chronic overnutrition is a prominent pathophysiological mechanism in obesity-induced metabolic disease. Increased disposal of FAs is therefore an attractive strategy for intervening in obesity and related disorders. Skeletal muscle uncoupling protein 3 (UCP3) activity is associated with increased FA oxidation and antagonizes weight gain in mice on obesogenic diets, but the mechanisms involved are not clear. Here, we show that UCP3 forms a direct, FA-stimulated, mitochondrial matrix-localized complex with the auxiliary unsaturated FA-metabolizing enzyme, {Delta}3,5-{Delta}2,4dienoyl-CoA-isomerase (ECH1). Expression studies in C2C12 myoblasts that functionally augments state 4 (uncoupled) respiration and FA oxidation in skeletal myocytes.\n\nMechanistic studies indicate that ECH1:UCP3 complex formation is likely stimulated by FA import into the mitochondria to enhance uncoupled respiration and unsaturated FA oxidation in mouse skeletal myocytes. In order to characterize the contribution of ECH1-dependent FA metabolism in NST, we generated an ECH1 knockout mouse and found that these mice were severely cold intolerant, despite an up-regulation of UCP3 expression in SKM. These findings illuminate a novel mechanism that links unsaturated FA metabolism with mitochondrial uncoupling and non-shivering thermogenesis in SKM.

biochemistry↗