Muscle atrophy is a growing concern, particularly in older adults and people with sedentary lifestyles. Because treatment options are limited, extensive research is crucial to discover novel therapeutic agents. Thus, we investigated the effect of 3-(4-hydroxy-3-methoxyphenyl) propionic acid (HMPA) and its parent compound, 4-hydroxy-3-methoxycinnamic acid (HMCA), on dexamethasone (Dex)-induced muscle atrophy in C57BL/6J female mice. Dex injection (10 mg/kg body weight [BW] in mice for 10 consecutive days negatively affected body weight, gastrocnemius and tibialis anterior muscle mass, myofiber cross sectional area (CSA) and level of myosin heavy chain (MyHC) protein. Atrogin-1 and muscle ring finger protein-1, two major muscle atrophy-associated ubiquitin ligases, were significantly increased following Dex administration, along with their upstream regulators forkhead box O3a (FoxO3a) and Krüppel-like factor 15 (KLF15). Furthermore, Dex-induced oxidative stress by increasing malondialdehyde and advanced oxidation protein products in plasma and skeletal muscle. Intriguingly, HMPA and HMCA administration (50 mg/kg BW) for 21 days effectively prevented the attenuation of muscle mass, myofiber CSA and MyHC protein levels and suppressed ubiquitin ligase expression by ameliorating the upstream transcriptional factors FoxO3a and KLF15. Moreover, increased oxidative stress and oxidative stress-sensitive casitas B-lineage lymphoma proto-oncogene-b (Cbl-b) ubiquitin ligase induced by Dex were effectively diminished by HMPA/HMCA administration. These observations suggest that HMPA and HMCA may be potential in vivo therapeutic agents that attenuate muscle atrophy by reversing atrophy-mimicking genes, oxidative stress, and related anomalies.

This study investigated the efficacy of two natural compounds-celastrol, a heat shock protein (HSP) inducer, and Cblin peptide, a ubiquitination inhibitor-in counteracting muscle atrophy under real microgravity conditions. Both agents independently attenuated microgravity-induced reductions in myotube thickness, myosin heavy chain protein levels, and atrogene expression. Celastrol primarily enhanced HSP expression, whereas Cblin peptide inhibited insulin receptor substrate-1 degradation, thereby promoting insulin-like growth factor-1 signaling. Despite their distinct molecular actions, no synergistic or additive effects were observed when combined. These findings highlight the potential of celastrol and Cblin peptide as functional ingredients for mitigating muscle atrophy, particularly in the context of space travel. Notably, Cblin peptide is abundant in glycinin-rich soybean protein, and celastrol is derived from the root of Tripterygium wilfordii (Taiwan vine). Future applications may include incorporating these plant-derived compounds into space foods to improve the quality of life for astronauts in space.NEW & NOTEWORTHY This study evaluated the effects of celastrol and the Cblin peptide in mitigating muscle atrophy under microgravity conditions. Both compounds alleviated myotube atrophy through distinct mechanisms, though no synergistic effect was observed. Celastrol upregulated heat shock protein (HSP) expression, whereas Cblin prevented IRS-1 degradation, thereby enhancing IGF-1 signaling. Sourced from Tripterygium wilfordii and soybean protein, respectively, these agents may serve as functional space foods to help counteract muscle atrophy and support astronauts' health during spaceflight.

3-(4-Hydroxy-3-methoxyphenyl) propionic acid is an in vivo metabolite of 4-hydroxy-3-methoxycinnamic acid which is abundantly found in coffee bean, rice bran, fruits, and vegetables. Previous studies reported that polyphenols and their metabolites exhibit positive effects on muscle health. Thus, the effect of 3-(4-hydroxy-3-methoxyphenyl) propionic acid on muscle atrophy induced by dexamethasone was investigated using mouse C2C12 skeletal myotubes. Dexamethasone treatment (10 mu M) reduced the diameter and myosin heavy chain protein expression in C2C12 myotubes; it also increased muscle atrophy-associated ubiquitin ligases, such as muscle atrophy F-box protein 1/Atrogin-1 and muscle ring finger protein-1, along with their upstream regulator Kr & uuml;ppel-like factor 15. Dexamethasone dephosphorylated FoxO3a transcription factor and increased total FoxO3a expression. Interestingly, 10 mu M 3-(4-hydroxy-3-methoxyphenyl) propionic acid treatment significantly attenuated dexamethasone-induced reduction in myotube thickness and muscle protein degradation and suppressed muscle atrophy-associated ubiquitin ligases. 3-(4-Hydroxy-3-methoxyphenyl) propionic acid also prevented dexamethasone-induced Kr & uuml;ppel-like factor 15 and FoxO3a expression. In conclusion, these results suggest that in vivo metabolite of polyphenols per se could be the real origin of the anti-muscular atrophy activity, as 3-(4-hydroxy-3-methoxyphenyl) propionic acid ameliorated glucocorticoid-induced muscle atrophy by suppressing Atrogin-1 and MuRF-1.

Muscle atrophy, characterized by a decline in muscle mass and function, has limited treatment options, highlighting the need for further research. In this study, we investigated the effect of carnosine, a dipeptide with well-established antioxidant properties, on dexamethasone (Dex)-induced muscle atrophy in female C57BL/6J mice. Dex (10 mg/kg body weight) reduced muscle weight, cross-sectional area (CSA), and myosin heavy chain (MyHC) protein expression, while elevating the expression of the muscle atrophy-related ubiquitin ligases Atrogin-1 and Muscle RING-finger protein-1 (MuRF1). Dex also increased oxidative stress, leading to upregulation of the oxidative stress-sensitive ubiquitin ligase Cbl-b and downregulation of IRS-1. Notably, a 21-day treatment with carnosine (300 mg/kg body weight) significantly mitigated Dex-induced reductions in muscle mass, myofiber CSA, and MyHC protein, while suppressing ubiquitin ligase expression and preserving IRS-1 levels. Carnosine likewise decreased oxidative stress and the associated Cbl-b upregulation. These findings suggest that carnosine is a promising therapeutic candidate for managing Dex-induced muscle atrophy.

Skeletal muscle dynamically regulates protein synthesis and degradation through metabolic responses to external stimuli. In the absence of mechanical load, this normal metabolic response is impaired, leading to muscle atrophy. Previous studies have suggested that mitochondrial dysfunction occurs under unloaded conditions. In this study, we focused on aconitase 2 (Aco2), a mitochondrial protein known to contain an iron-sulfur cluster and function as a metabolic sensor. We generated skeletal muscle-specific Aco2 knockout (cKO) mice to investigate its role in muscle function. Although these mice appeared grossly normal, they died shortly after birth. Analysis of the diaphragm muscle revealed signs of muscle fiber atrophy and impaired muscle maturation. Besides these signs of immaturity, abnormal muscle cells exhibiting disrupted sarcomere structures were frequently observed. Furthermore, these cells showed a marked increase in the apoptotic marker Active Caspase-3, indicating that Aco2 deficiency induces muscle cell death. These findings suggest that Aco2 plays a critical role in skeletal muscle maturation and maintenance of muscle homeostasis. Moreover, these findings highlighted the potential involvement of Aco2 in disuse muscle atrophy and its utility as a therapeutic target.

Soy glycinin contains a functional inhibitory sequence, DIpYNP, against muscle-atrophy-associated ubiquitin ligase Cbl-b. It inhibited the binding of Cbl-b and IRS-1 (called Cblin-like peptide) and improved denervation-induced muscle atrophy in mice. In the present study, we evaluated the anti-muscle atrophy effect by feeding Kori-tofu to a mouse model of muscle atrophy induced by sciatic nerve transection, because Kori-tofu is a freeze-dried tofu made mainly from soy proteins. In the mice fed with Kori-tofu for one week, no significant inhibition in the reduction of the tibialis anterior (TA), gastrocnemius (GA) or soleus (SOL) muscle due to denervation was observed, compared with those of mice fed a soy protein isolate (SPI) or casein. However, in the TA muscle of the Kori-tofu-fed group, a significant suppression of the increased expression levels of muscle atrophy-related genes, MAFbx/atrogin-1 and MuRF-1, induced by denervation was observed similarly as that of mice fed a SPI. Additionally, the denervation-mediated decrease in the fast-twitch type myosin heavy chain (MyHC) level was suppressed in the TA of the Kori-tofu-fed group. Thus, our results suggest that Kori-tofu could be a useful and perishable functional space food against unloading-mediated muscle atrophy.

This study investigated the protective effect of carnosine and its components (L-histidine and beta-alanine [HA]) against dexamethasone (Dex)-induced muscle atrophy in C2C12 myotubes. Myotubes were treated with Dex (10 mu M) to induce muscle atrophy manifested by decreased myotube diameter, low myosin heavy chain content, and increased expression of muscle atrophy-associated ubiquitin ligases (Atrogin-1, MuRF-1, and Cbl-b). Carnosine (20 mM) treatment significantly improved the myotube diameter and MyHC protein expression level in Dex-treated C2C12 myotubes. It also downregulated the expression of Atrogin-1, MuRF-1, and Cbl-b and suppressed the expression of forkhead box O3 (FoxO3a) mediated by Dex. Furthermore, reactive oxygen species production was increased by Dex but was ameliorated by carnosine treatment. However, HA (20 mM), the component of carnosine, treatment was found ineffective in preventing Dex-induced protein damage. Therefore, based on above results it can be suggested that carnosine could be a potential therapeutic agent to prevent Dex-induced muscle atrophy compared to its components HA.

This study investigated the effect of morin, a flavonoid, on dexamethasone-induced muscle atrophy in C57BL/6J female mice. Dexamethasone (10 mg/kg body weight) for 10 days significantly reduced body weight, gastrocnemius and tibialis anterior muscle mass, and muscle protein in mice. Dexamethasone significantly upregulated muscle atrophy-associated ubiquitin ligases, including atrogin-1 and MuRF-1, and the upstream transcription factors FoxO3a and Klf15. Additionally, dexamethasone significantly induced the expression of oxidative stress-sensitive ubiquitin ligase Cbl-b and the accumulation of the oxidative stress markers malondialdehyde and advanced protein oxidation products in both the plasma and skeletal muscle samples. Intriguingly, morin treatment (20 mg/kg body weight) for 17 days effectively attenuated the loss of muscle mass and muscle protein and suppressed the expression of ubiquitin ligases while reducing the expression of upstream transcriptional factors. Therefore, morin might act as a potential therapeutic agent to attenuate muscle atrophy by modulating atrophy-inducing genes and preventing oxidative stress.

Various dietary protein supplements are used by the elderly and bedridden to maintain their skeletal muscle mass and functions. High-quality proteins act as an anabolic driver and help to improve muscle strength and performance. Previously, we reported that soy protein significantly attenuates denervation-induced loss of muscle mass and myofiber cross sectional area in mice with inhibition of ubiquitination and degradation of IRS-1 in tibialis anterior muscle. It also increased muscle volume and strength in bedridden patients. In the present study, we investigated the effects of dietary soybean supplementation on muscle functions in taxi drivers lacking vigorous physical exercise. We conducted a case-control study on 25 healthy, male taxi drivers between the ages of 36 and 71 y performing minimal physical exercise. They were divided into two dietary groups: the soybean diet group (n=13) who ate daily meals (dinner) supplemented with 50 g of steamed soybean for 30 d and the control diet group (n=12) who received no soybean supplement. Next, we measured the muscle cross-sectional area (CSA) and muscle strength and function in both the groups before and after 30 d of soybean intake. The body weights of both diet groups did not differ significantly over time. However, after 30 d of soybean supplementation, the soybean-fed group developed significantly higher muscle CSA and grip strength compared to the control groups. In conclusion, dietary soybean supplementation improved muscle function in taxi drivers who lacked exercise.

Recent studies show that muscle mass and metabolic function are interlinked. Muscle RING finger 1 (MuRF1) is a critical muscle-specific ubiquitin ligase associated with muscle atrophy. Yet, the molecular target of MuRF1 in atrophy and aging remains unclear. We examined the role of MuRF1 in aging, using MuRF1-deficient (MuRF1-/- ) mice in vivo, and MuRF1-overexpressing cell in vitro. MuRF1 deficiency partially prevents age-induced skeletal muscle loss in mice. Interestingly, body weight and fat mass of more than 7-month-old MuRF1-/- mice were lower than in MuRF1+/+ mice. Serum and muscle metabolic parameters and results of indirect calorimetry suggest significantly higher energy expenditure and enhanced lipid metabolism in 3-month-old MuRF1-/- mice than in MuRF1+/+ mice, resulting in suppressed adipose tissue gain during aging. Pyruvate dehydrogenase kinase 4 (PDK4) is crucial for a switch from glucose to lipid metabolism, and the interaction between MuRF1 and PDK4 was examined. PDK4 protein levels were elevated in mitochondria from the skeletal muscle in MuRF1-/- mice. In vitro, MuRF1 interacted with PDK4 but did not induce degradation through ubiquitination. Instead, SUMO posttranscriptional modification (SUMOylation) of PDK4 was detected in MuRF1-overexpressing cells, in contrast to cells without the RING domain of MuRF1. MuRF1 deficiency enhances lipid metabolism possibly by upregulating PDK4 localization into mitochondrial through prevention of SUMOylation. Inhibition of MuRF1-mediated PDK4 SUMOylation is a potential therapeutic target for age-related dysfunction of lipid metabolism and muscle atrophy.

We previously reported that intramuscular injections of ubiquitin ligase CBLB inhibitory pentapeptide (Cblin; Asp-Gly-pTyr-Met-Pro) restored lost muscle mass caused by sciatic denervation. Here, we detected Cblin on the basolateral side of Caco-2 cells after being placed on the apical side, and found that cytochalasin D, a tight junction opener, enhanced Cblin transport. Orally administered Cblin was found in rat plasma, indicating that intact Cblin was absorbed in vitro and in vivo. Furthermore, transgenic Cblin peptide-enriched rice (CbR) prevented the denervation-induced loss of muscle mass and the upregulation of muscle atrophy-related ubiquitin ligases in mice. These findings indicated that CbR could serve as an alternative treatment for muscle atrophy.

Skeletal muscle atrophy is the decrease in muscle mass and strength caused by reduced protein synthesis/accelerated protein degradation. Various conditions, such as denervation, disuse, aging, chronic diseases, heart disease, obstructive lung disease, diabetes, renal failure, AIDS, sepsis, cancer, and steroidal medications, can cause muscle atrophy. Mechanistically, inflammation, oxidative stress, and mitochondrial dysfunction are among the major contributors to muscle atrophy, by modulating signaling pathways that regulate muscle homeostasis. To prevent muscle catabolism and enhance muscle anabolism, several natural and synthetic compounds have been investigated. Recently, polyphenols (i.e., natural phytochemicals) have received extensive attention regarding their effect on muscle atrophy because of their potent antioxidant and anti-inflammatory properties. Numerous in vitro and in vivo studies have reported polyphenols as strongly effective bioactive molecules that attenuate muscle atrophy and enhance muscle health. This review describes polyphenols as promising bioactive molecules that impede muscle atrophy induced by various proatrophic factors. The effects of each class/subclass of polyphenolic compounds regarding protection against the muscle disorders induced by various pathological/physiological factors are summarized in tabular form and discussed. Although considerable variations in antiatrophic potencies and mechanisms were observed among structurally diverse polyphenolic compounds, they are vital factors to be considered in muscle atrophy prevention strategies.

Infection of certain influenza viruses is triggered when its 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, whereas 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↓ 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 α-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.

Aims and Objective: Various studies revealed the antioxidant and anti-inflammatory properties of Psidium guajava leaves. This present study reported the anti-inflammatory and protective effects of Psidium guajava leaves on Carbon tetrachloride (CCl4) induced rat liver. Methods: In this study, Long Evans female rats (150-180 g) were divided into four groups. CCl4 in olive oil was given orally by gavage at a dose of 1 mL/kg and Psidium guajava leave powder was provided as 2.5% w/w of food. Liver marker enzyme activity was monitored by evaluating the alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Alkaline Phosphatases (ALP) in plasma. The plasma and liver tissue concentrations of thiobarbituric acid reactive substances (TBARS), Nitric Oxide (NO), advanced protein oxidation product (APOP), glutathione (GSH, in reduced form) and activity of catalase were measured as an oxidative stress marker. Results: The results of this study suggested the serum transferase activities were increased in CCl4 administered rat, which was normalized by Psidium guajava leaves supplementation. Moreover, oxidative stress markers were significantly reduced and antioxidant enzyme activity was significantly improved by Psidium guajava leaves supplementation in CCl4 administered rat. Hematoxylin and Eosin and Picrosirius Red staining of liver section revealed reduced inflammatory cell infiltration and fibrosis, respectively by Psidium guajava leaves supplementation in CCl4 administered rats. Conclusion: In conclusion, Psidium guajava leaves may prevent liver damage and inflammation in CCl4-administered rats, which indicated strong antioxidant capacity. Thus, Psidium guajava leaves could be a source of natural antioxidants. Further study is required for using Psidium guajava leaves in the clinical case of liver dysfunction.

Glucocorticoids are the drugs most commonly used to manage inflammatory diseases. However, they are prone to inducing muscle atrophy by increasing muscle proteolysis and decreasing protein synthesis. Various studies have demonstrated that antioxidants can mitigate glucocorticoid-induced skeletal muscle atrophy. Here, we investigated the effect of a potent antioxidative natural flavonoid, morin, on the muscle atrophy and oxidative stress induced by dexamethasone (Dex) using mouse C2C12 skeletal myotubes. Dex (10 μM) enhanced the production of reactive oxygen species (ROS) in C2C12 myotubes via glucocorticoid receptor. Moreover, Dex administration reduced the diameter and expression levels of the myosin heavy chain protein in C2C12 myotubes, together with the upregulation of muscle atrophy-associated ubiquitin ligases, such as muscle atrophy F-box protein 1/atrogin-1, muscle ring finger protein-1, and casitas B-lineage lymphoma proto-oncogene-b. Dex also significantly decreased phosphorylated Foxo3a and increased total Foxo3a expression. Interestingly, Dex-induced ROS accumulation and Foxo3a expression were inhibited by morin (10 μM) pretreatment. Morin also prevented the Dex-induced reduction of myotube thickness, together with muscle protein degradation and suppression of the upregulation of atrophy-associated ubiquitin ligases. In conclusion, our results suggest that morin effectively prevents glucocorticoid-induced muscle atrophy by reducing oxidative stress.

The aim of this study was to examine the effect of rosuvastatin in experimentally-induced hepatic inflammation and fibrosis in rats. Carbon tetra chloride (CCl4) was administered orally to induce liver damage in female Long Evans rats. Rats were treated with CCl4 alone twice a week over two weeks. Rosuvastatin (10 mg/kg) was also given daily to CCl4 treated rats concurrently by nasogastric gavage. After two weeks, various oxidative stress markers as well as liver markers enzymes were investigated in different animal groups tested in this study. Moreover, histological assessments were also done for inflammatory cell infiltration and fibrosis in the liver of all test groups. Plasma aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) activities were increased in the CCl4 group compared with the control group. Increased liver enzyme activities were significantly decreased by rosuvastatin treatment. Moreover, rosuvastatin treatment inhibited the formation of lipid peroxidation products in CCl4 administered rats. Rosuvastatin treatment also restored the decreased superoxide dismutase (SOD) activities as well as elevated the reduced glutathione concentration in CCl4 administered rats. Liver tissues from rats of control group also revealed no significant pathological changes, while CCl4 administered rats showed significant infiltration of inflammatory cells and liver fibrosis, which was further, normalized or significantly decreased by rosuvastatin treatment. This study revealed that, rosuvastatin treatment may ameliorate all necroinflammatory and fibrotic changes in liver tissues of CCl4 induced rats and could be used as an alternative therapy for chemical or drug-induced liver fibrosis. [ J Adv Biotechnol Exp Ther 2020; 3(1.000): 01-08]

We evaluated the cardioprotective effect of Aloe vera gel isoprenaline (ISO)-administered myocardial infarction in rats. ISO administration increased lipid peroxidation and oxidative stress in rats, which were ameliorated by A. vera gel supplementation. Our study also revealed that creatine kinase-MB (CK-MB) activities were increased in ISO-administered rats, while the activities of cellular antioxidants, such as superoxide dismutase and catalase, and glutathione concentration were decreased. A. vera gel lowered CK-MB enzyme activities and the glutathione concentration in ISO-administered rats, and increased antioxidant activities. Histopathological examination also revealed increases in thickness of the left ventricle myocardium, increases in mononuclear cell infiltrations, increased degeneration of focal areas of the endocardium, and increased fibrous tissue deposition in the heart of ISO-administered rats; whereas, A. vera prevented infiltration of inflammatory cells and reduced left ventricular fibrosis. In conclusion, we show that A. vera supplementation protects against development of cardiac inflammation, fibrosis, and oxidative stress in ISO-administered rats.

The present investigation was conducted to evaluate the effect of Citrus maxima fruit peel supplementation in alloxan-induced diabetic rats. Diabetes was induced in male Long Evans rats by intraperitoneal injection of alloxan monohydrate (90 mg/kg body weight). Blood glucose level, oral glucose tolerance, and liver enzyme markers were evaluated. Moreover, histopathological examinations were also conducted using in liver sections to examine inflammation and fibrosis in the liver. Alloxan administered animals showed significant body weight loss and poor glucose tolerance. Alloxan administration also increased the liver marker enzymes' activities and increased oxidative stress parameters compared to control rats. Citrus maxima fruit peel supplementation for 21 days significantly (p < 0.05) reverted the glucose intolerance and liver enzymes activities to near normal levels. Moreover, Citrus maxima fruit peel supplementation prevented oxidative stress in liver of alloxan-induced diabetic rats. Our investigation also showed that alloxan administration in rats causes inflammatory cells' infiltration and fibrosis in the liver which is ameliorated by Citrus maxima fruit peel supplementation. Our investigation suggests that Citrus maxima fruit peel supplementation can ameliorate alloxan-induced diabetes and its complications. The antioxidant properties of the fruit probably play a major role in the observed effects.

Citrus macroptera has been used as a culinary fruit and medicinal plant in traditional medicine system in Bangladesh. The aim of the present study was to evaluate the presence of phenolic compounds in Citrus macroptera peel powder and the protective effect of Citrus macroptera against carbon tetrachloride (CCl4)-induced liver injury in rats.