Biology subjects

Eshima, H.

Publications and source records attributed to Eshima, H..

6 recordsLinked to original sources

bioRxiv2024

Deuterium-reinforced polyunsaturated fatty acids protect against muscle atrophy induced by type 1 diabetes in mice

HIGHLIGHTSO_LID-PUFA diet prevents muscle atrophy in STZ-induced diabetic mice. C_LIO_LID-PUFA diet prevents muscle weakness depending on increased calcium release in STZ-induced diabetic mice. C_LIO_LID-PUFA diet may show a trend to decrease blood glucose in STZ-induced diabetic mice. C_LIO_LID-PUFA diet does not alter ferroptosis-related protein profiles including ACSL4, LPCAT3, ALOX12, and Gpx4. C_LI Oxidative stress and reactive oxygen species (ROS) have been linked to muscle atrophy and weakness. Diabetes increases the oxidative status of lipoproteins in nearly all tissues, including muscle tissues, but the role of lipid ROS on diabetes-induced muscle atrophy is not fully understood. Deuterium reinforced polyunsaturated fatty acids (D-PUFA) are more resistant to ROS-initiated chain reaction of lipid peroxidation than regular hydrogenated PUFA (H-PUFA). In this study, we tested the hypothesis that D-PUFA would protect muscle atrophy induced by diabetes driven by an accumulation of lipid hydroperoxides (LOOH). C57BL/6J mice were dosed with H-PUFA or D-PUFA for four weeks through dietary supplementation and then injected with streptozotocin (STZ) to induce insulin-deficient diabetes. After two weeks, muscles tissues were analyzed for individual muscle mass, force generating capacity and cross-sectional area. Skeletal muscle fibers from diabetic mice exhibited increased total ROS and LOOH. This was abolished by the D-PUFA supplementation regardless of accumulated iron. D-PUFA were found to be protective against muscle atrophy and weakness from STZ-induced diabetes. Prevention of muscle atrophy and weakness by D-PUFA might be independent of ACSL4/LPCAT3/15-LOX pathway. These findings provide novel insights into the role of LOOH in the mechanistic link between oxidative stress and diabetic myopathy and suggest a novel therapeutic approach to diabetes-associated muscle weakness.

pathology↗

bioRxiv2023

Lipid peroxidation does not mediate muscle atrophy induced by PSD deficiency

Mechanisms by which disuse promotes skeletal muscle atrophy is not well understood. We previously demonstrated that disuse reduces the abundance of mitochondrial phosphatidylethanolamine (PE) in skeletal muscle. Deletion of phosphatidylserine decarboxylase (PSD), an enzyme that generates mitochondrial PE, was sufficient to promote muscle atrophy. In this study, we tested the hypothesis that muscle atrophy induced by PSD deletion is driven by an accumulation of lipid hydroperoxides (LOOH). Mice with muscle-specific knockout of PSD (PSD-MKO) were crossed with glutathione peroxidase 4 (GPx4) transgenic mice (GPx4Tg) to suppress the accumulation of LOOH. However, PSD-MKO x GPx4Tg mice and PSD-MKO mice demonstrated equally robust loss of muscle mass. These results suggest that muscle atrophy induced by PSD deficiency is not driven by the accumulation of LOOH.

physiology↗

bioRxiv2023

Inhibition of skeletal muscle Lands cycle ameliorates weakness induced by physical inactivity

BackgroundLipid hydroperoxides (LOOH) have been implicated in skeletal muscle atrophy with age and disuse. Lysophosphatidylcholine acyltransferase 3 (LPCAT3), an enzyme of Lands cycle, conjugates a polyunsaturated fatty acyl chain to a lysophospholipid (PUFA-PL) molecule, providing substrates for LOOH propagation. Previous studies suggest that inhibition of Lands cycle is an effective strategy to suppress LOOH. Mice with skeletal muscle-specific tamoxifen-inducible knockout of LPCAT3 (LPCAT3-MKO) were utilized to determine if muscle-specific attenuation of LOOH may alleviate muscle atrophy and weakness with disuse. MethodsLPCAT3-MKO and control mice underwent 7 days of sham or hindlimb unloading (HU model) to study muscle mass and force-generating capacity. LOOH was assessed by quantifying 4-hydroxynonenal (4-HNE)-conjugated peptides. Quantitative PCR and lipid mass spectrometry were used to validate LPCAT3 deletion. Results7 days of HU was sufficient to induce muscle atrophy and weakness concomitant to an increase in 4-HNE. Deletion of LPCAT3 reversed HU-induced increase in muscle 4HNE. No difference was found in body mass, body composition, or caloric intake between genotypes. The soleus (SOL) and plantaris (PLANT) muscles of the LPCAT3-MKO mice were partially protected from atrophy compared to controls, concomitant to attenuated decrease in cross-sectional areas in type I and IIa fibers. Strikingly, SOL and extensor digitorum longus (EDL) were robustly protected from HU-induced reduction in force-generating capacity in the LPCAT3-MKO mice compared to controls. ConclusionOur findings demonstrate that attenuation of muscle LOOH is sufficient to restore skeletal muscle function, in particular a protection from reduction in muscle specific force. Thus, muscle LOOH contributes to atrophy and weakness induced by HU in mice.

physiology↗

bioRxiv2022

Phosphatidylethanolamine facilitates mitochondrial pyruvate entry to regulate metabolic flexibility

Carbohydrates and lipids provide the majority of substrates to fuel mitochondrial oxidative phosphorylation (OXPHOS). Metabolic inflexibility, defined as an impaired ability to switch between these fuels, is implicated in a number of metabolic diseases. Here we explore the mechanism by which physical inactivity promotes metabolic inflexibility in skeletal muscle. We developed a mouse model of sedentariness by small mouse cage (SMC) that, unlike other classic models of disuse in mice, faithfully recapitulates metabolic responses that occur in humans. Bioenergetic phenotyping of mitochondria displayed metabolic inflexibility induced by physical inactivity, demonstrated by a reduction in pyruvate-stimulated respiration (JO2) in absence of a change in palmitate-stimulated JO2. Pyruvate resistance in these mitochondria was likely driven by a decrease in phosphatidylethanolamine (PE) abundance in the mitochondrial membrane. Reduction in mitochondrial PE by deletion of phosphatidylserine decarboxylase (PSD) was sufficient to induce metabolic inflexibility measured at the whole-body level, as well as at the level of skeletal muscle mitochondria. Low mitochondrial PE was sufficient to increase glucose flux towards lactate. We further implicate that resistance to pyruvate metabolism is due to attenuated mitochondrial entry via mitochondrial pyruvate carrier (MPC). These findings suggest a novel mechanism by which mitochondrial PE directly regulates MPC activity to modulate metabolic flexibility.

physiology↗

bioRxiv2021

Lipid hydroperoxides promote muscle atrophy through lysosomal amplification

Reactive oxygen species (ROS) accumulation is a cardinal feature of skeletal muscle atrophy. ROS refers to a collection of radical molecules whose cellular signals are vast, and it is unclear which downstream consequences of ROS are responsible for the loss of muscle mass and strength. Here we show that lipid hydroperoxides (LOOH) are increased with age and disuse, and the accumulation of LOOH by deletion of glutathione peroxidase 4 (GPx4) is sufficient to augment muscle atrophy. LOOH promoted atrophy in a lysosomal-dependent, proteasomal-independent manner. In young and old mice, genetic and pharmacologic neutralization of LOOH or their secondary reactive lipid aldehydes robustly prevented muscle atrophy and weakness, indicating that LOOH-derived carbonyl stress mediate age- and disuse-induced muscle dysfunction. Our findings provide novel insights for the role of LOOH in sarcopenia including a therapeutic implication by pharmacologic suppression.

physiology↗

bioRxiv2019

Mitochondrial PE potentiates respiratory enzymes to amplify skeletal muscle aerobic capacity

Exercise capacity is a strong predictor of all-cause mortality. Skeletal muscle mitochondrial respiratory capacity, its biggest contributor, adapts robustly to changes in energy demands induced by contractile activity. While transcriptional regulation of mitochondrial enzymes has been extensively studied, there is limited information on how mitochondrial membrane lipids are regulated. Herein, we show that exercise training or muscle disuse alters mitochondrial membrane phospholipids including phosphatidylethanolamine (PE). Addition of PE promoted, whereas removal of PE diminished, mitochondrial respiratory capacity. Surprisingly, skeletal muscle-specific inhibition of mitochondrial-autonomous synthesis of PE caused a respiratory failure due to metabolic insults in the diaphragm muscle. While mitochondrial PE deficiency coincided with increased oxidative stress, neutralization of the latter did not rescue lethality. These findings highlight the previously underappreciated role of mitochondrial membrane phospholipids in dynamically controlling skeletal muscle energetics and function.

physiology↗