Gracilaria chorda attenuates obesity-related muscle wasting through activation of SIRT1/PGC1α in skeletal muscle of mice.

Gracilaria chorda (GC) is a red algal species that is primarily consumed in Asia. Here, we investigated the effect of GC on obesity-related skeletal muscle wasting. Furthermore, elucidating its impact on the activation of sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptor gamma coactivator 1α (PGC1α) constituted a critical aspect in understanding the underlying mechanism of action. In this study, 6-week-old male C57BL/6 mice were fed a high-fat diet (HFD) for 8 weeks to induce obesity, then continued on the HFD for another 8 weeks while orally administered GC. GC decreased ectopic fat accumulation in skeletal muscle and increased muscle weight, size, and function in obese mice. Furthermore, GC reduced skeletal muscle atrophy and increased hypertrophy in mice. We hypothesized that the activation of SIRT1/PGC1α by GC regulates skeletal muscle atrophy and hypertrophy. We observed that GC increased the expression of SIRT1 and PGC1α in skeletal muscle of mice and in C2C12 cells, which increased mitochondrial function and biogenesis. In addition, when C2C12 cells were treated with the SIRT1-specific inhibitor EX-527, no changes were observed in the protein levels of SIRT1 and PGC1α in the GC-treated C2C12 cells. Therefore, GC attenuated obesity-related muscle wasting by improving mitochondrial function and biogenesis through the activation of SIRT1/PGC1α in the skeletal muscle of mice.

Gromwell ameliorates glucocorticoid-induced muscle atrophy through the regulation of Akt/mTOR pathway.

BACKGROUND: Muscle atrophy is characterized by decreased muscle mass, function, and strength. Synthetic glucocorticoids, including dexamethasone (Dexa), are commonly used to treat autoimmune diseases. However, prolonged exposure of Dexa with high dose exerts severe side effects, including muscle atrophy. The purpose of this study was to investigate whether Gromwell root extract (GW) can prevent Dexa-induced muscle atrophy in C2C12 cells and mice and to characterize the composition of GW to identify bioactive compounds. METHODS: For in vitro experiments, GW (0.5 and 1 µg/mL) or lithospermic acid (LA, 5 and 10 µM) was added to C2C12 myotubes on day 4 of differentiation and incubated for 24 h, along with 50 µM Dexa. For in vivo experiment, four-week-old male C57BL/6 mice were randomly divided into the four following groups (n = 7/group): Con group, Dexa group, GW0.1 group, and GW0.2 group. Mice were fed experimental diets of AIN-93 M with or without 0.1 or 0.2% GW for 4 weeks. Subsequently, muscle atrophy was induced by administering an intraperitoneal injection of Dexa at a dose of 15 mg/kg/day for 38 days, in conjunction with dietary intake. RESULTS: In Dexa-induced myotube atrophy, treatment with GW increased myotube diameter, reduced the expression of muscle atrophy markers, and enhanced the expression of myosin heavy chain (MHC) isoforms in C2C12 cells. Supplementation with the GW improved muscle function and performance in mice with Dexa-induced muscle atrophy, evidenced in the grip strength and running tests. The GW group showed increased lean body mass, skeletal muscle mass, size, and myosin heavy chain isoform expression, along with reduced skeletal muscle atrophy markers in Dexa-injected mice. Supplementation with GW increased protein synthesis and decreased protein degradation through the Akt/mammalian target of rapamycin and glucocorticoid receptor/forkhead box O3 signaling pathways, respectively. We identified LA as a potential bioactive component of the GW. LA treatment increased myotube diameter and decreased the expression of muscle atrophy markers in Dexa-induced C2C12 cells. CONCLUSIONS: These findings underscore the potential of the GW in preventing Dexa-induced skeletal muscle atrophy and highlight the contribution of LA to its effects.

Gromwell (Lithospermum erythrorhizon) Attenuates High-Fat-Induced Skeletal Muscle Wasting by Increasing Protein Synthesis and Mitochondrial Biogenesis.

Gromwell (Lithospermum erythrorhizon, LE) can mitigate obesity-induced skeletal muscle atrophy in C2C12 myotubes and high-fat diet (HFD)-induced obese mice. The purpose of this study was to investigate the anti-skeletal muscle atrophy effects of LE and the underlying molecular mechanism. C2C12 myotubes were pretreated with LE or shikonin, and active component of LE, for 24 h and then treated with 500 µM palmitic acid (PA) for an additional 24 h. Additionally, mice were fed a HFD for 8 weeks to induced obesity, and then fed either the same diet or a version containing 0.25% LE for 10 weeks. LE attenuated PA-induced myotubes atrophy in differentiated C2C12 myotubes. The supplementation of LE to obese mice significantly increased skeletal muscle weight, lean body mass, muscle strength, and exercise performance compared with those in the HFD group. LE supplementation not only suppressed obesity-induced skeletal muscle lipid accumulation, but also downregulated TNF-α and atrophic genes. LE increased protein synthesis in the skeletal muscle via the mTOR pathway. We observed LE induced increase of mitochondrial biogenesis and upregulation of oxidative phosphorylation related genes in the skeletal muscles. Furthermore, LE increased the expression of peroxisome proliferator-activated receptor-gamma coactivator-1 alpha and the phosphorylation of adenosine monophosphate-activated protein kinase. Collectively, LE may be useful in ameliorating the detrimental effects of obesity-induced skeletal muscle atrophy through the increase of protein synthesis and mitochondrial biogenesis of skeletal muscle.

Nutritional approaches targeting mitochondria for the prevention of sarcopenia.

A decline in function and loss of mass, a condition known as sarcopenia, is observed in the skeletal muscles with aging. Sarcopenia has a negative effect on the quality of life of elderly. Individuals with sarcopenia are at particular risk for adverse outcomes, such as reduced mobility, fall-related injuries, and type 2 diabetes mellitus. Although the pathogenesis of sarcopenia is multifaceted, mitochondrial dysfunction is regarded as a major contributor for muscle aging. Hence, the development of preventive and therapeutic strategies to improve mitochondrial function during aging is imperative for sarcopenia treatment. However, effective and specific drugs that can be used for the treatment are not yet approved. Instead studies on the relationship between food intake and muscle aging have suggested that nutritional intake or dietary control could be an alternative approach for the amelioration of muscle aging. This narrative review approaches various nutritional components and diets as a treatment for sarcopenia by modulating mitochondrial homeostasis and improving mitochondria. Age-related changes in mitochondrial function and the molecular mechanisms that help improve mitochondrial homeostasis are discussed, and the nutritional components and diet that modulate these molecular mechanisms are addressed.

Fuzhuan brick tea extract ameliorates obesity-induced skeletal muscle atrophy by alleviating mitochondrial dysfunction in mice.

Fuzhuan brick tea (FBT) is a post-fermented tea fermented by the fungus Eurotium cristatum and is mainly produced in Hunan Province, China. Our previous study revealed that FBT extract prevents obesity by increasing energy expenditure and mitochondrial content in mice. Therefore, in this study, we hypothesized that FBT extract could be effective in alleviating obesity-induced muscle atrophy by addressing mitochondrial dysfunction, and aimed to explore the underlying molecular mechanism of FBT extract in high-fat diet-induced obese mice. FBT extract increased skeletal muscle weight and size, myosin heavy chain isoforms, and muscle performance in obese mice. Additionally, FBT extract reduced obesity-induced intramuscular lipids, skeletal muscle inflammation, and the expression of skeletal muscle atrophy markers, and increased the expression of fibronectin type III domain-containing protein 5 in skeletal muscles. Obesity-induced skeletal muscle mitochondrial dysfunction was improved by FBT extract as analyzed through mitochondrial morphology, fatty acid oxidation, respiratory chain complexes, and mitochondrial dynamics and biogenesis. Epigallocatechin, a major bioactive compound in FBT extract, attenuated palmitic acid-induced muscle atrophy by regulating mitochondrial functions in C2C12 cells. In conclusion, FBT extract may prevent obesity-induced muscle atrophy by alleviating mitochondrial dysfunction in mice.

6-Gingerol Ameliorates Adiposity and Inflammation in Adipose Tissue in High Fat Diet-Induced Obese Mice: Association with Regulating of Adipokines.

We investigated the effects of 6-gingerol on adiposity and obesity-induced inflammation by focusing on the regulation of adipogenesis and adipokines in white adipose tissue (WAT) of diet-induced obese mice. C57BL/6 mice were fed a high-fat diet (HFD) containing 0.05% 6-gingerol for 8 weeks. 6-Gingerol supplementation significantly reduced body weight, WAT mass, serum triglyceride, leptin and insulin levels, and HOMA-IR in HFD-fed mice. Additionally, the size of adipocytes in epididymal fat pads was reduced in HFD-fed mice by 6-gingerol supplementation. 6-Gingerol reduced the mRNA and protein levels of adipogenesis-related transcription factors, such as SREBP-1, PPARγ, and C/EBPα in WAT. Furthermore, 6-gingerol suppressed the expression of lipogenesis-related genes, such as fatty acid synthase and CD36 in WAT. Adiponectin expression was significantly increased, whereas inflammatory adipokines (leptin, resistin, TNF-α, MCP-1, and PAI-1) and the macrophage marker F4/80 were significantly reduced in the WAT of HFD-fed mice by 6-gingerol supplementation. In conclusion, 6-gingerol effectively contributed to the alleviation of adiposity and inflammation in WAT, which is associated with the regulation of adipokines in diet-induced obese mice.

Millet seed oil activates ß-catenin signaling and promotes hair growth.

Alopecia, regardless of gender, exacerbates psychological stress in those affected. The rising prevalence of alopecia has fueled a research interest in preventing hair loss. This study investigates the potential of millet seed oil (MSO) in promoting the proliferation of hair follicle dermal papilla cells (HFDPC) and stimulating hair growth in animals with testosterone-dependent hair growth inhibition as part of a study on dietary treatments to improve hair growth. MSO-treated HFDPC significantly increased cell proliferation and phosphorylation of AKT, S6K1, and GSK3ß proteins. This induces ß-catenin, a downstream transcription factor, to translocate to the nucleus and increase the expression of factors related to cell growth. In a C57BL/6 mice model in which hair growth was inhibited by subcutaneous testosterone injection after shaving the dorsal skin, oral administration of MSO stimulated hair growth in the subject mice by increasing the size and number of hair follicles. These results suggest that MSO is a potent agent that may help prevent or treat androgenetic alopecia by promoting hair growth.

The innate immune signaling component FBXC-58 mediates dietary restriction effects on healthy aging in Caenorhabditis elegans.

Dietary restriction (DR) is a highly effective and reproducible intervention that prolongs longevity in many organisms. The molecular mechanism of action of DR is tightly connected with the immune system; however, the detailed mechanisms and effective downstream factors of immunity that mediate the beneficial effects of DR on aging remain unknown. Here, to investigate the immune signaling that mediates DR effects, we used Caenorhabditis elegans, which has been widely used in research, to understand the underlying molecular mechanisms of aging and immunity. We found that the F-box gene, fbxc-58, a regulator of the innate immune response, is a novel mediator of DR effects on extending the health span of C. elegans. fbxc-58 is upregulated by DR and is necessary for DR-induced lifespan extension and physical health improvement in C. elegans. Furthermore, through DR, fbxc-58 prevents disintegration of the mitochondrial network in body wall muscle during aging. We found that fbxc-58 is a downstream target of the ZIP-2 and PHA-4 transcription factors, the well-known DR mediator, and fbxc-58 extends longevity in DR through an S6 kinase-dependent pathway. We propose that the novel DR effector, fbxc-58, could provide a new mechanistic understanding of the effects of DR on healthy aging and elucidate the signaling mechanisms that link immunity and DR effects with aging.

Codium fragile reduces adipose tissue expansion and fatty liver incidence by downregulating adipo- and lipogenesis.

Codium fragile (C. fragile) is a marine alga with high functional food potential. Recent studies have proven C. fragile extract (CFE) effective against obesity. However, the exact underlying mechanism of CFE's anti-obesity effects remains unclear. Herein, CFE was orally administered to male C57BL/6 mice for 7 weeks, along with a high-fat diet. CFE (100 mg/kg) effectively induced weight loss, lowered serum cholesterol levels, and suppressed adipocyte differentiation in white adipose tissue (WAT). Furthermore, CFE effectively reduced hepatic total triglyceride, cholesterol, and lipid levels, while significantly improving liver size and color. mRNA expression analysis in WAT and liver tissue revealed that CFE significantly suppressed the expression of PPARγ and aP-2 in adipocyte differentiation, and SREBP-1c and FAS in de novo lipogenesis, suggesting that CFE's anti-obesity effect is exerted by gene inhibition. PRACTICAL APPLICATIONS: Research on marine plants with anti-obesity effects has been increasing recently. This study demonstrated that C. fragile extract (CFE) is effective in reducing body weight and suppressing adipocyte differentiation, along with the improvement of fatty liver in mice fed with a high-fat diet (HFD). The anti-obesity effect of CFE was exhibited by the down-regulation of adipogenesis and lipogenesis, respectively. Based on these results, C. fragile could be useful, not only to effectively combat obesity but also in improving obesity-induced liver dysfunction.

Castor Oil Plant (Ricinus communis L.) Leaves Improve Dexamethasone-Induced Muscle Atrophy via Nrf2 Activation.

Skeletal muscle atrophy is characterized by reduced muscle function and size. Oxidative stress contributes to muscle atrophy but can be treated with antioxidants. This study investigated the antioxidant activity of a castor oil plant leaf (Ricinus communis L.) extract (RC) and its effects on muscle atrophy. Rutin was identified as the major compound among the thirty compounds identified in RC via LC-MS/MS and was found to inhibit dexamethasone (DEX)-induced muscle atrophy and mitochondrial oxidative stress. Rutin-rich RC showed DPPH and ABTS radical scavenging activities and efficiently reduced the DEX-induced myotube atrophy and mitochondrial oxidative damage in C2C12 cells. RC supplementation prevented the loss of muscle function and muscle mass in DEX-administered mice and ameliorated DEX-induced oxidative stress via Nrf2 signaling. Taken together, both RC and rutin ameliorated muscle atrophy and helped in maintaining redox homeostasis; hence, rutin-rich RC could be a promising functional food that is beneficial for muscle health.

Fruit of Schisandra chinensis and its bioactive component schizandrin B ameliorate obesity-induced skeletal muscle atrophy.

Schisandra chinensis fruit (Omiza in Korean), used for the production tea or liquor, and is known to enhance skeletal muscle function. However, the effect of Omiza extract (OM) on obesity-induced skeletal muscle atrophy remains unclear. This study investigated the effect of OM on skeletal muscle mass and performance in obese mice. OM increased skeletal muscle weight, size and improved skeletal muscle performance. Further, it also suppressed obesity-induced increases in proinflammatory cytokines, MuRF1, and Atrogin1 in mouse skeletal muscle and enhanced the expression of MHC and the phosphorylation of AKT/mTOR signaling molecules, thereby suppressing myostatin expression and regulating Smad-FOXO signaling. Schizandrin B, a major component of OM inhibited palmitic acid induced atrophy in C2C12 cells via Smad-FOXO regulation, suggesting that it partially contributed to the effects of OM against obesity-induced muscle atrophy. Taken together, OM may have the potential to prevent and treat obesity-induced muscle atrophy.

Antioxidant Activity of Valeriana fauriei Protects against Dexamethasone-Induced Muscle Atrophy.

Skeletal muscle atrophy is defined as wasting or loss of muscle. Although glucocorticoids (GCs) are well-known anti-inflammatory drugs, their long-term or high-dose use induces skeletal muscle atrophy. Valeriana fauriei (VF) is used to treat restlessness, anxiety, and sleep disorders; however, its effects on skeletal muscle health have not been investigated. This study investigated whether Valeriana fauriei could ameliorate muscle atrophy. We induced muscle atrophy in vitro and in vivo, by treatment with dexamethasone (DEX), a synthetic GC. In DEX-induced myotube atrophy, Valeriana fauriei treatment increased the fusion index and decreased the expression of muscle atrophic genes such as muscle atrophy F-box (MAFbx/Atrogin-1) and muscle RING-finger protein 1 (MuRF1). In DEX-treated mice with muscle atrophy, Valeriana fauriei supplementation increased the ability to exercise, muscle weight, and cross-sectional area, whereas it inhibited myosin heavy chain isoform transition and the expression of muscle atrophy biomarkers. Valeriana fauriei treatment led to via the downregulation of muscle atrophic genes via inhibition of GC receptor translocation. Valeriana fauriei was also found to act as a reactive oxygen species (ROS) scavenger. Didrovaltrate (DI), an iridoid compound from Valeriana fauriei, was found to downregulate atrophic genes and decrease ROS in the DEX-induced myotube atrophy. Consolidated, our results indicate that Valeriana fauriei prevents DEX-induced muscle atrophy by inhibiting GC receptor translocation. Further, Valeriana fauriei acts as a ROS scavenger, and its functional compound is didrovaltrate. We suggest that Valeriana fauriei and its functional compound didrovaltrate possess therapeutic potentials against muscle atrophy.

Mitochondrial dysfunction in skeletal muscle contributes to the development of acute insulin resistance in mice.

BACKGROUND: Although mounting evidence indicates that insulin resistance (IR) co-occurs with mitochondrial dysfunction in skeletal muscle, there is no clear causal link between mitochondrial dysfunction and IR pathogenesis. In this study, the exact role of mitochondria in IR development was determined. METHODS: Six-week-old C57BL/6 mice were fed a high-fat diet for 2 weeks to induce acute IR or for 24 weeks to induce chronic IR (n = 8 per group). To characterize mitochondrial function, we measured citrate synthase activity, ATP content, mitochondrial DNA (mtDNA) content, and oxygen consumption rate in gastrocnemius and liver tissues. We intraperitoneally administered mitochondrial division inhibitor 1 (mdivi-1) to mice with acute IR and measured mitochondrial adaptive responses such as mitophagy, mitochondrial unfolded protein response (UPRmt), and oxidative stress (n = 6 per group). RESULTS: Acute IR occurred coincidently with impaired mitochondrial function, including reduced citrate synthase activity (-37.8%, P < 0.01), ATP production (-88.0%, P < 0.01), mtDNA (-53.1%, P < 0.01), and mitochondrial respiration (-52.2% for maximal respiration, P < 0.05) in skeletal muscle but not in liver. Administration of mdivi-1 attenuated IR development by increasing mitochondrial function (+58.5% for mtDNA content, P < 0.01; 4.06 ± 0.69 to 5.84 ± 0.95 pmol/min/mg for citrate synthase activity, P < 0.05; 13.06 ± 0.70 to 34.87 ± 0.70 pmol/min/g for maximal respiration, P < 0.001). Western blot analysis showed acute IR resulted in increased autophagy (mitophagy) and UPRmt induction in muscle tissue. This adaptive response was inhibited by mdivi-1, which reduced the mitochondrial oxidative stress of skeletal muscle during acute IR. CONCLUSIONS: Acute IR induced mitochondrial oxidative stress that impaired mitochondrial function in skeletal muscle. Improving mitochondrial function has important potential for treating acute IR.

2,6-Dimethoxy-1,4-benzoquinone increases skeletal muscle mass and performance by regulating AKT/mTOR signaling and mitochondrial function.

BACKGROUND: 2,6-Dimethoxy-1,4-benzoquinone (DMBQ), a natural phytochemical present in fermented wheat germ, has been reported to exert anti-cancer, anti-inflammatory, and anti-adipogenic effects. However, the effect of DMBQ on muscle hypertrophy and myoblast differentiation has not been elucidated. PURPOSE: We investigated the effect of DMBQ on skeletal muscle mass and muscle function and then determined the possible mechanism of DMBQ. METHODS: To examine myogenic differentiation and hypertrophy, confluent C2C12 cells were incubated in differentiation medium with or without various concentrations of DMBQ for 4 days. In animal experiments, C57BL/6 mice were fed DMBQ-containing AIN-93 diet for 7 weeks. Grip strength, treadmill, microscopic evaluation of muscle tissue, western blotting, and quantitative real-time PCR were performed. RESULTS: DMBQ significantly increased fusion index, myotube size, and the protein expression of myosin heavy chain (MHC). DMBQ increased the phosphorylation of protein kinase B (AKT) and p70 ribosomal protein S6 kinase (S6K), whereas the phosphorylation of these proteins was abolished by the phosphoinositide 3-kinase inhibitor LY294002 in C2C12 cells. In addition, DMBQ treatment increased peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1α), which programs mitochondrial biogenesis, protein levels compared with control C2C12 cells. DMBQ significantly increased maximal respiration and spare respiratory capacity in C2C12 cells. In animal experiments, DMBQ increased skeletal muscle weights and skeletal muscle fiber size compared with the control group values. In addition, the DMBQ group showed increased grip strength and running distance on an accelerating treadmill. The protein expression of total MHC, MHC1, MHC2A, and MHC2B in skeletal muscle was upregulated by DMBQ supplementation. We found that DMBQ increased the phosphorylation of AKT and mammalian target of rapamycin (mTOR), as well as downstream S6K and eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) in skeletal muscle. DMBQ also stimulated mRNA expression of PGC1α, accompanied by an increase in mitochondrial DNA content, oxidative phosphorylation (OXPHOS) proteins, and oxidative enzyme activity. CONCLUSION: Collectively, DMBQ was shown to increase skeletal muscle mass and performance by regulating the AKT/mTOR signaling pathway and enhancing mitochondrial function, which might be useful for the treatment and prevention of skeletal muscle atrophy.

γ-Oryzanol Improves Exercise Endurance and Muscle Strength by Upregulating PPARδ and ERRγ Activity in Aged Mice.

SCOPE: γ-Oryzanol, a well-known antioxidant, has been used by body builders and athletes to boost strength and increase muscle gain, without major side effects. However, the effect of γ-Oryzanol on sarcopenia and the underlying molecular mechanism is poorly understood. RESULTS: Aged mice fed with the γ-Oryzanol diet do not show significant changes in muscle weight, but show increased running endurance as well as improved grip strength. The expression and activity of PPARδ and ERRγ are increased in skeletal muscle of γ-Oryzanol supplemented mice. γ-Oryzanol upregulates oxidative muscle fibers by MEF2 transcription factor, and PGC-1α and ERRα expressions. Fatty acid oxidation related genes and mitochondria biogenesis are upregulated by γ-Oryzanol. In addition, γ-Oryzanol inhibits TGF-ß-Smad-NADPH oxidase 4 pathway and inflammatory cytokines such as TNF-α, IL-1ß, IL-6, and p65 NF-κB subunit, which cause skeletal muscle weakness. Collectively, γ-Oryzanol attenuates muscle weakness pathway and increases oxidative capacity by increasing PPARδ and ERRγ activity, which contributes to enhance strength and improve oxidative capacity in muscles, consequently enhancing exercise capacity in aged mice. Particularly, γ-Oryzanol directly binds to PPARδ. CONCLUSIONS: These are the first findings showing that γ-Oryzanol enhances skeletal muscle function in aged mice by regulating PPARδ and ERRγ activity without muscle gain.

Identifying Codium fragile extract components and their effects on muscle weight and exercise endurance.

Codium fragile (CF) is a type of green algae consumed as kimchi in Asia. UPLC-QTOF-MS/MS analysis showed that CF contain lysophosphatidyl choline, canthaxanthin, retinoic acid, α-tocopherol, and unsaturated fatty acids, which reportedly improve skeletal muscle health. However, the effect of CF on skeletal muscle mass and function remains to be elucidated. In mice fed with CF extracts, exercise endurance and muscle weight increased. CF extracts enhanced protein synthesis and myogenic differentiation through the mTORC1 pathway. CF extracts also promoted oxidative muscle fiber formation and mitochondrial biogenesis through the PGC-1α-related signaling pathway. Upregulation of PGC-1α by CF extracts was abolished by EX527 SIRT1 inhibitor treatment. Changed signaling molecules in the CF extracts were partially regulated by canthaxanthin, a new compound in CF extracts, suggesting that canthaxanthin contribute synergistically to the effect of CF extracts. Therefore, CF is a potential food source for sport nutrition or prevention of sarcopenia.

MiR-141-3p promotes mitochondrial dysfunction in ovariectomy-induced sarcopenia via targeting Fkbp5 and Fibin.

Post-menopausal conditions exacerbate the biological aging process and this is often accompanied by visceral adiposity with sarcopenia. Mitochondrial impairment is a hallmark of frailty and sarcopenia in the elderly. However, the exact mechanism underlying the development of obesogenic sarcopenia and the involvement of mitochondria remains unclear. This study confirmed that there is a decline in muscle mass and function as well as mitochondrial dysfunction in the quadriceps of ovariectomized (OVX) mice. To investigate the role of microRNA (miRNA) in this process, we performed miRNA and mRNA arrays and found that miR-141-3p directly targets and downregulates FK506 binding protein 5 (Fkbp5) and Fibin. Overexpression of miR-141-3p decreased mitochondrial function and inhibited myogenic differentiation in C2C12 cells. These effects were mediated by Fkbp5 and Fibin inhibition. Conversely, knockdown of miR-141-3p increased mitochondrial respiration and enhanced myogenesis. Treatment with ß-estradiol effectively reversed the palmitic acid-induced upregulation of miR-141-3p and subsequent downregulation of Fkbp5 and Fibin. In conclusion, miR-141-3p is upregulated in OVX mice, and this is associated with mitochondrial dysfunction through inhibition of Fkbp5 and Fibin. These findings suggest that inhibiting miR-141-3p could be a therapeutic target for alleviating obesogenic sarcopenia.

Withaferin A exerts an anti-obesity effect by increasing energy expenditure through thermogenic gene expression in high-fat diet-fed obese mice.

BACKGROUND: The enhancement of energy expenditure has attracted attention as a therapeutic target for the management of body weight. Withaferin A (WFA), a major constituent of Withania somnifera extract, has been reported to possess anti-obesity properties, however the underlying mechanism remains unknown. PURPOSE: To investigate whether WFA exerts anti-obesity effects via increased energy expenditure, and if so, to characterize the underlying pathway. METHODS: C57BL/6 J mice were fed a high-fat diet (HFD) for 10 weeks, and WFA was orally administered for 7 days. The oxygen consumption rate of mice was measured at 9 weeks using an OxyletPro™ system. Hematoxylin and eosin (H&E), immunohistochemistry, immunoblotting, and real-time PCR methods were used. RESULTS: Treatment with WFA ameliorated HFD-induced obesity by increasing energy expenditure by improving of mitochondrial activity in brown adipose tissue (BAT) and promotion of subcutaneous white adipose tissue (scWAT) browning via increasing uncoupling protein 1 levels. WFA administration also significantly increased AMP-activated protein kinase (AMPK) phosphorylation in the BAT of obese mice. Additionally, WFA activated mitogen-activated protein kinase (MAPK) signaling, including p38/extracellular signal-regulated kinase MAPK, in both BAT and scWAT. CONCLUSION: WFA enhances energy expenditure and ameliorates obesity via the induction of AMPK and activating p38/extracellular signal-regulated kinase MAPK, which triggers mitochondrial biogenesis and browning-related gene expression.

Chrysanthemum zawadskil Herbich attenuates dexamethasone-induced muscle atrophy through the regulation of proteostasis and mitochondrial function.

Chrysanthemum zawadskii Herbich (CZH) is used in traditional medicine to treat inflammatory diseases and diabetes. However, the effects of CZH on muscle wasting remains to be studied. Here, we investigated the effect of CZH on dexamethasone (DEX), a synthetic glucocorticoid, induced muscle atrophy. To examine the effect of CZH on muscle atrophy, C2C12 myotubes were co-treated with DEX and CZH for 24 h. The treatment with CZH prevented DEX-induced myotube atrophy in a dose-dependent manner. CZH inhibited the DEX-induced decrease of the MHC isoforms and the upregulation of atrogin-1 and MuRF1 in C2C12 differentiated cells. C57BL/6 mice were supplemented with 0.1 % CZH for 8 weeks, with DEX-induced muscle atrophy stimulated in the last 3 weeks. In the mice, CZH supplementation effectively reversed DEX-induced skeletal muscle atrophy and increased the exercise capacity of the mice through the inhibition of glucocorticoid receptor translocation. Additionally, we observed that DEX-evoked impaired proteostasis was ameliorated via the Akt/mTOR pathway. CZH also prevented the DEX-induced decrease in the mitochondrial respiration. HPLC analysis demonstrated the highest concentration of acacetin-7-O-ß-d-rutinoside (AR) among 4 compounds. Moreover, AR, a functional compound of CZH, prevented DEX-evoked muscle atrophy. Thus, we suggest that CZH could be a potential therapeutic candidate against muscle atrophy and AR is the main functional compound of CZH.

Mir214-3p and Hnf4a/Hnf4α reciprocally regulate Ulk1 expression and autophagy in nonalcoholic hepatic steatosis.

Macroautophagy/autophagy, a self-degradative process, regulates metabolic homeostasis in response to various stress conditions and is a therapeutic target for nonalcoholic fatty liver disease. We found that autophagic activity was inhibited as a result of a significant reduction in the expression of autophagy-related genes such as Ulk1 in a mouse model and patients with fatty liver. This downregulation was caused by increased Mir214-3p levels and decreased Hnf4a/Hnf4α mRNA levels in hepatocytes. Mir214-3p suppressed Ulk1 expression through direct binding at a 3' untranslated region sequence. Hnf4a directly activated transcription of Ulk1. We investigated lipid accumulation and the expression of autophagy-related genes in the livers of mice treated with anti-Mir214-3p. Hepatic steatosis was alleviated, and Ulk1 mRNA levels were significantly increased by locked nucleic acid-mediated Mir214-3p silencing. Additionally, autophagosome formation and MAP1LC3/LC3-II protein levels were increased, indicating an increase in autophagic activity. Interestingly, suppression of Mir214-3p did not ameliorate fatty liver under Ulk1 suppression, suggesting that reduced Mir214-3p levels mitigate hepatic steatosis through upregulation of Ulk1. These results demonstrate that inhibition of Mir214-3p expression ameliorated fatty liver disease through increased autophagic activity by increasing the expression of Ulk1. Thus, Mir214-3p is a potential therapeutic target for nonalcoholic fatty disease.Abbreviations: AMPK: adenosine monophosphate-activated protein kinase; ATG: autophagy-related; ChIP: chromatin immunoprecipitation; CTSB: cathepsin B; CTSL: cathepsin L; CQ: chloroquine; HFD: high-fat diet; HNF4A: hepatocyte nuclear factor 4, alpha; IF: immunofluorescence; IHC: immunohistochemistry; LDs: lipid droplets; Leup: leupeptin; LFD: low-fat diet; LNA: locked nucleic acid; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; miRNA: microRNA; MTOR: mechanistic target of rapamycin kinase; NAFLD: non-alcoholic fatty liver disease; NASH: non-alcoholic steatohepatitis; PCR: polymerase chain reaction; TEM: transmission electron microscopy; TF: transcription factor; TLDA: TaqMan low-density array; ULK1: unc-51 like kinase 1; UTR: untranslated region.