scholarly journals Dihydromyricetin Attenuates Dexamethasone-Induced Muscle Atrophy by Improving Mitochondrial Function via the PGC-1α Pathway

2018 ◽  
Vol 49 (2) ◽  
pp. 758-779 ◽  
Author(s):  
Yujie Huang ◽  
Ka Chen ◽  
Qingbo Ren ◽  
Long Yi ◽  
Jundong Zhu ◽  
...  
Keyword(s):  
Muscle Atrophy ◽  
Mitochondrial Function ◽  
Chain Complex ◽  
Mitochondrial Respiratory Chain ◽  
Mitochondrial Morphology ◽  
Cross Sectional ◽  
Mitochondrial Respiratory Chain Complex ◽  
Underlying Mechanisms ◽  
Complex Activities

Background/Aims: Skeletal muscle atrophy is an important health issue and can impose tremendous economic burdens on healthcare systems. Glucocorticoids (GCs) are well-known factors that result in muscle atrophy observed in numerous pathological conditions. Therefore, the development of effective and safe therapeutic strategies for GC-induced muscle atrophy has significant clinical implications. Some natural compounds have been shown to effectively prevent muscle atrophy under several wasting conditions. Dihydromyricetin (DM), the most abundant flavonoid in Ampelopsis grossedentata, has a broad range of health benefits, but its effects on muscle atrophy are unclear. The purpose of this study was to evaluate the effects and underlying mechanisms of DM on muscle atrophy induced by the synthetic GC dexamethasone (Dex). Methods: The effects of DM on Dex-induced muscle atrophy were assessed in Sprague-Dawley rats and L6 myotubes. Muscle mass and myofiber cross-sectional areas were analyzed in gastrocnemius muscles. Muscle function was evaluated by a grip strength test. Myosin heavy chain (MHC) content and myotube diameter were measured in myotubes. Mitochondrial morphology was observed by transmission electron microscopy and confocal laser scanning microscopy. Mitochondrial DNA (mtDNA) was quantified by real-time PCR. Mitochondrial respiratory chain complex activities were examined using the MitoProfile Rapid Microplate Assay Kit, and mitochondrial membrane potential was assessed by JC-1 staining. Protein levels of mitochondrial biogenesis and dynamics markers were detected by western blotting. Myotubes were transfected with siRNAs targeting peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), mitochondrial transcription factor A (TFAM) and mitofusin-2 (mfn2) to determine the underlying mechanisms. Results: In vivo, DM preserved muscles from weight and average fiber cross-sectional area losses and improved grip strength. In vitro, DM prevented the decrease in MHC content and myotube diameter. Moreover, DM stimulated mitochondrial biogenesis and promoted mitochondrial fusion, rescued the reduced mtDNA content, improved mitochondrial morphology, prevented the collapse in mitochondrial membrane potential and enhanced mitochondrial respiratory chain complex activities; these changes restored mitochondrial function and improved protein metabolism, contributing to the prevention of Dex-induced muscle atrophy. Furthermore, the protective effects of DM on mitochondrial function and muscle atrophy were alleviated by PGC-1α siRNA, TFAM siRNA and mfn2 siRNA transfection in vitro. Conclusion: DM attenuated Dex-induced muscle atrophy by reversing mitochondrial dysfunction, which was partially mediated by the PGC-1α/TFAM and PGC-1α/mfn2 signaling pathways. Our findings may open new avenues for identifying natural compounds that improve mitochondrial function as promising candidates for the management of muscle atrophy.

Dietary dimethylglycine sodium salt supplementation improves growth performance, redox status, and skeletal muscle function of intrauterine growth restriction weaned piglets

2021 ◽  
Author(s):  
Kaiwen Bai ◽  
Luyi Jiang ◽  
Qiming Li ◽  
Jingfei Zhang ◽  
Lili Zhang ◽  
...  
Keyword(s):  
Growth Performance ◽  
Mitochondrial Function ◽  
Chain Complex ◽  
Basal Diet ◽  
Mitochondrial Respiratory Chain ◽  
Redox Status ◽  
Weaned Piglets ◽  
Complex Activity ◽  
Mitochondrial Respiratory Chain Complex ◽  
Intrauterine Growth

Abstract Few studies have focused on the role of dimethylglycine sodium salt (DMG-Na) in protecting the redox status of skeletal muscle, although it is reported to be beneficial in animal husbandry. This study investigated the beneficial effects of DMG-Na on the growth performance, longissimus dorsi muscle (LM) redox status, and mitochondrial function in weaning piglets that were intrauterine growth restricted (IUGR). Ten normal birth weight (NBW) newborn piglets (1.53 ± 0.04 kg) and 20 IUGR newborn piglets (0.76 ± 0.06 kg) from ten sows were obtained. All piglets were weaned at 21 days of age and allocated to three groups with ten replicates per group: NBW-weaned piglets fed a common basal diet (N); IUGR weaned piglets fed a common basal diet (I); IUGR weaned piglets fed a common basal diet supplemented with 0.1% DMG-Na (ID). They were slaughtered at 49 days of age to collect the serum and LM samples. Compared with the N group, the growth performance, LM structure, serum, and, within the LM, mitochondrial redox status, mitochondrial respiratory chain complex activity, energy metabolites, redox status-related, cell adhesion-related, and mitochondrial function-related gene expression, and protein expression deteriorated in group I (P < 0.05). The ID group showed improved growth performance, LM structure, serum, and, within the LM, mitochondrial redox status, mitochondrial respiratory chain complex activity, energy metabolites, redox status-related, cell adhesion-related, and mitochondrial function-related gene expression, and protein expression compared with those in the I group (P < 0.05). The above results indicated that the DMG-Na treatment could improve the LM redox status and mitochondrial function in IUGR weaned piglets via the Nuclear factor erythroid 2-related factor 2 (Nrf2)/ Sirtuin 1 (SIRT1)/ Peroxisome proliferator-activated receptorγcoactivator-1α (PGC1α) network, thus improving their growth performance.

scholarly journals Astaxanthin extends lifespan via altered biogenesis of the mitochondrial respiratory chain complex III

2019 ◽  
Author(s):  
Ronit Hoffman ◽  
Laure D. Sultan ◽  
Ann Saada ◽  
Joseph Hirschberg ◽  
Oren Osterzetser-Biran ◽  
...  
Keyword(s):  
Model Organism ◽  
Chain Complex ◽  
Mitochondrial Respiratory Chain ◽  
Industrial Applications ◽  
Complex Iii ◽  
Life Extension ◽  
Mitochondrial Respiratory Chain Complex ◽  
C Elegans ◽  
Species Effect

AbstractAstaxanthin is a keto-carotenoid produced in some bacteria and algae, which has very important industrial applications (i.e., in cosmetics, coloring additive in aquaculture and as a dietary supplement for human). Here, we analyzed the molecular basis of Astaxanthin-mediated prolongevity in the model organism, Caenorhabditis elegans. The increased lifespan effects of Astaxanthin are restricted in C. elegans to the adult phase and are uninfluenced by various other carotenoids tested. Genetic analyses indicated that the Astaxanthin-mediated life-extension relies on mitochondria activity, via the Rieske iron-sulfur polypeptide-1 (ISP-1), but is not influenced by the functions of other known longevity-related gene-loci, including CLK-1, DAF-2, DAT-16, EAT-2, GAS-1 GLP-1 or MEV-1. Biochemical analyses of native respiratory complexes showed that Astaxanthin affects the biogenesis of holo-complex III (and likely supercomplex I+III, as well). Effects on holo-CIII assembly and activity were also indicated by in-vitro assays, with mitochondria isolated from worms, rodents, human and plants, which were treated with Astaxanthin. These data indicated a cross-species effect on the oxidative phosphorylation (OXPHOS) machinery by the carotenoid, and provide with further insights into the molecular mechanism of animals longevity extension by Astaxanthin.Significance StatementAstaxanthin is a widely consumed pigment by animals and human. In this study we find that Astaxanthin, but not other tested carotenoids, significantly extends the lifespan of animals by affecting respiratory complex III (CIII) biogenesis of the mitochondria, in plants, C. elegans, rodents and human. We further propose a model to try explaining this effect of astaxanthin on animals’ longevity.

Primary defects in lipid handling and resistance to exercise in myotubes from obese donors with and without type 2 diabetes

2020 ◽  
Vol 45 (2) ◽  
pp. 169-179 ◽  
Author(s):  
Nils Gunnar Løvsletten ◽  
Arild C. Rustan ◽  
Claire Laurens ◽  
G. Hege Thoresen ◽  
Cedric Moro ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Chain Complex ◽  
Mitochondrial Respiratory Chain ◽  
Oxidative Capacity ◽  
Mitochondrial Respiratory Chain Complex ◽  
Electrical Pulse Stimulation ◽  
Palmitate Uptake ◽  
Reduced Rate

Several studies have shown that human primary myotubes retain the metabolic characteristic of their donors in vitro. We have demonstrated, along with other researchers, a reduced lipid turnover and fat oxidation rate in myotubes derived from obese donors with and without type 2 diabetes (T2D). Because exercise is known to increase fat oxidative capacity in skeletal muscle, we investigated if in vitro exercise could restore primary defects in lipid handling in myotubes of obese individuals with and without T2D compared with lean nondiabetic donors. Primary myotubes cultures were derived from biopsies of lean, obese, and T2D subjects. One single bout of long-duration exercise was mimicked in vitro by electrical pulse stimulation (EPS) for 24 h. Lipid handling was measured using radiolabeled palmitate, metabolic gene expression by real-time qPCR, and proteins by Western blot. We first showed that myotubes from obese and T2D donors had increased uptake and incomplete oxidation of palmitate. This was associated with reduced mitochondrial respiratory chain complex II, III, and IV protein expression in myotubes from obese and T2D subjects. EPS stimulated palmitate oxidation in lean donors, while myotubes from obese and T2D donors were refractory to this effect. Interestingly, EPS increased total palmitate uptake in myotubes from lean donors while myotubes from T2D donors had a reduced rate of palmitate uptake into complex lipids and triacylglycerols. Novelty Myotubes from obese and T2D donors are characterized by primary defects in palmitic acid handling. Both obese and T2D myotubes are partially refractory to the beneficial effect of exercise on lipid handling.

scholarly journals Opa1 overexpression protects from early onset Mpv17-/--related mouse kidney disease

2020 ◽  
Author(s):  
Marta Luna-Sanchez ◽  
Cristiane Benincà ◽  
Raffaele Cerutti ◽  
Gloria Brea-Calvo ◽  
Anna Yeates ◽  
...  
Keyword(s):  
Focal Segmental Glomerulosclerosis ◽  
Late Onset ◽  
Chain Complex ◽  
Mitochondrial Respiratory Chain ◽  
Clinical Feature ◽  
Mitochondrial Morphology ◽  
Mitochondrial Respiratory Chain Complex ◽  
Mtdna Depletion ◽  
Segmental Glomerulosclerosis ◽  
Genetically Determined

AbstractModerate overexpression of Opa1, encoding a master regulator of mitochondrial cristae morphology, has been shown to improve significantly mitochondrial damage induced by drugs, surgical denervation, or genetically determined OXPHOS defects. However, this approach has been so far demonstrated in a limited number of genetically defective OXPHOS models characterized by specific impairment of a single mitochondrial respiratory chain complex. Here, we investigated the effectiveness of moderate Opa1 overexpression in the Mpv17-/- mouse, characterized by profound, multisystem mtDNA depletion. In naïve Mpv17-/- individuals, whose genetic background was crossed with individuals belonging to the Opa1tg strain, we found a surprising anticipation of severe, progressive focal segmental glomerulosclerosis, previously described in Mpv17-/- animals as a late-onset clinical feature (after 12-18 months of life). In contrast, kidney failure led Mpv17-/- individuals from this new “mixed” strain leading to death 8-9 weeks after birth. However, Mpv17-/-::Opa1tg mice lived much longer than Mpv17-/- littermates, and developed much later severe proteinuria associated with focal segmental glomerulosclerosis. MtDNA content and OXPHOS activities were significantly higher in Mpv17-/-::Opa1tg than in Mpv17-/- kidneys, and similar to WT littermates. Mitochondrial network and cristae ultrastructure were largely preserved in Mpv17-/-::Opa1tg vs. Mpv17-/- kidney and isolated podocytes. Mechanistically, the protective effect of Opa1 overexpression in this model was mediated by a block in apoptosis due to the stabilization of the mitochondrial cristae, consequently increasing the levels of mitochondrial morphology proteins like MFN2 and MIC19 as well as stabilizing ATP synthase oligomers. These results demonstrate that strategies aiming at increasing Opa1 expression or activity can be an effective aid against mtDNA depletion syndromes.

scholarly journals FAM92A1 is a BAR domain protein required for mitochondrial ultrastructure and function

2018 ◽  
Vol 218 (1) ◽  
pp. 97-111 ◽  
Author(s):  
Liang Wang ◽  
Ziyi Yan ◽  
Helena Vihinen ◽  
Ove Eriksson ◽  
Weihuan Wang ◽  
...  
Keyword(s):  
Mitochondrial Function ◽  
Molecular Mechanisms ◽  
Membrane Curvature ◽  
Mitochondrial Morphology ◽  
Membrane Remodeling ◽  
Mitochondrial Ultrastructure ◽  
Bar Domain ◽  
Bar Domain Proteins ◽  
Domain Protein

Mitochondrial function is closely linked to its dynamic membrane ultrastructure. The mitochondrial inner membrane (MIM) can form extensive membrane invaginations known as cristae, which contain the respiratory chain and ATP synthase for oxidative phosphorylation. The molecular mechanisms regulating mitochondrial ultrastructure remain poorly understood. The Bin-Amphiphysin-Rvs (BAR) domain proteins are central regulators of diverse cellular processes related to membrane remodeling and dynamics. Whether BAR domain proteins are involved in sculpting membranes in specific submitochondrial compartments is largely unknown. In this study, we report FAM92A1 as a novel BAR domain protein localizes to the matrix side of the MIM. Loss of FAM92A1 caused a severe disruption to mitochondrial morphology and ultrastructure, impairing organelle bioenergetics. Furthermore, FAM92A1 displayed a membrane-remodeling activity in vitro, inducing a high degree of membrane curvature. Collectively, our findings uncover a role for a BAR domain protein as a critical organizer of the mitochondrial ultrastructure that is indispensable for mitochondrial function.

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