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The present study aimed to investigate the effects of monotropein (MON) on improving dexamethasone (DEX)-induced muscle atrophy in mice and C2C12 mouse skeletal muscle cells. The body weights, grip strengths, and muscle weights of mice were assessed. The histological change in the gastrocnemius tissues was also observed through H&E staining. The expression of myosin heavy chain (MyHC), muscle ring finger 1 (MuRF1), and muscle atrophy F-box (Atrogin1) and the phosphorylation of AKT, mTOR, and FOXO3a in the muscle tissues of mice and C2C12 myotubes were analyzed using Western blotting. MON improved muscle atrophy in mice and C2C12 myotubes by regulating catabolic states via the AKT/mTOR/FOXO3a signaling pathways, and enhanced muscle function by the increases of muscle mass and strength in mice. This suggests that MON could be used for the prevention and treatment of muscle atrophy in patients. [ABSTRACT FROM AUTHOR]

Purpose: Left ventricular hypertrophy (LVH) is a cardiovascular complication highly prevalent in patients with chronic kidney disease (CKD). Previous studies analyzing 1α-hydroxylase or vitamin D receptor (Vdr) knockout mice revealed active vitamin D as a promising agent inhibiting LVH progression. Paricalcitol, an active vitamin D analog, failed to suppress the progression of LV mass index (LVMI) in pre-dialysis patients with CKD. As target genes of activated VDR differ depending on its agonists, we examined the effects of maxacalcitol (22-oxacalcitriol: OCT), a less calcemic active vitamin D analog, on LVH in hemodialysis patients and animal LVH models with renal insufficiency. Methods: In retrospective cohort study, patients treated with OCT who underwent hemodialysis were enrolled. Using cardiac echocardiography, LV mass was evaluated by the area-length method. In animal study, angiotensin II (Ang II)-infused Wister rats with heminephrectomy or Ang II-stimulated neonatal rat ventricular myocytes (NRVM) were treated with OCT. Results: OCT significantly inhibited the progression of LVMI in hemodialysis patients. In Ang II-infused heminephrectomized rats, OCT suppressed the progression of LVH in a blood pressure-independent manner. OCT also suppressed the activity of calcineurin in the left ventricle of model rats. Specifically, OCT reduced the protein levels of calcineurin A, but not the mRNA levels of Ppp3ca (calcineurin Aα). Luciferase assays showed that OCT increased the promoter activity of Fbxo32 (atrogin1), an E3 ubiquitin ligase targeting calcineurin A. Finally, OCT promoted ubiquitination and degradation of calcineurin A. Conclusion: Our works indicated that OCT retards progression of LVH through calcineurin-NFAT pathway, which reveal a novel aspect of OCT in attenuating pathological LVH. [ABSTRACT FROM AUTHOR]

The present study aimed to investigate the effects of monotropein (MON) on improving dexamethasone (DEX)-induced muscle atrophy in mice and C2C12 mouse skeletal muscle cells. The body weights, grip strengths, and muscle weights of mice were assessed. The histological change in the gastrocnemius tissues was also observed through H&E staining. The expression of myosin heavy chain (MyHC), muscle ring finger 1 (MuRF1), and muscle atrophy F-box (Atrogin1) and the phosphorylation of AKT, mTOR, and FOXO3a in the muscle tissues of mice and C2C12 myotubes were analyzed using Western blotting. MON improved muscle atrophy in mice and C2C12 myotubes by regulating catabolic states via the AKT/mTOR/FOXO3a signaling pathways, and enhanced muscle function by the increases of muscle mass and strength in mice. This suggests that MON could be used for the prevention and treatment of muscle atrophy in patients.

Muscle cachexia is a catabolic response, usually takes place in various fatal diseases, such as sepsis, burn injury, and chronic kidney disease. Muscle cachexia is also a common co-morbidity seen in the vast majority of advanced cancer patients, often associated with low quality of life and death due to general organ dysfunction. The triggering events and underlying molecular mechanisms of muscle wasting are not yet clearly defined. Our recent study has shown that the ectopic expression of Twist1 in muscle progenitor cells is sufficient to drive muscle structural protein breakdown and attendant muscle atrophy, reminiscent of muscle cachexia. Intriguingly, muscle Twist1 expression is highly induced in cachectic muscles from several mouse models of pancreatic ductal adenocarcinoma (PDAC), raising the interesting possibility that Twist1 may mediate PDAC-driven muscle cachexia. Along these lines, both genetic and pharmacological inactivation of Twist1 function was highly significant at protecting against cancer cachexia, which translated into a significant survival benefit in the experimental PDAC animals. From a translational perspective, elevated expression of Twist1 is also detected in cancer patients with severe muscle wasting, implicating a role of Twist1 in cancer cachexia, and further providing a possible target for therapeutic attenuation of cachexia to improve cancer patient survival. In this article, we will briefly summarize how Twist1 acts as a master regulator of tumor-induced cachexia, and discuss the relevance of our findings to muscle wasting diseases in general. The mechanism of decreased muscle mass in various catabolic conditions is thought to rely on similar pathways, and, therefore, Twist1-induced cancer cachexia may benefit diverse groups of patients with clinical complications associated with loss of muscle mass and functions, beyond the expected benefits for cancer patients.

Muscle cachexia is a catabolic response, usually takes place in various fatal diseases, such as sepsis, burn injury, and chronic kidney disease. Muscle cachexia is also a common co-morbidity seen in the vast majority of advanced cancer patients, often associated with low quality of life and death due to general organ dysfunction. The triggering events and underlying molecular mechanisms of muscle wasting are not yet clearly defined. Our recent study has shown that the ectopic expression of Twist1 in muscle progenitor cells is sufficient to drive muscle structural protein breakdown and attendant muscle atrophy, reminiscent of muscle cachexia. Intriguingly, muscle Twist1 expression is highly induced in cachectic muscles from several mouse models of pancreatic ductal adenocarcinoma (PDAC), raising the interesting possibility that Twist1 may mediate PDAC-driven muscle cachexia. Along these lines, both genetic and pharmacological inactivation of Twist1 function was highly significant at protecting against cancer cachexia, which translated into a significant survival benefit in the experimental PDAC animals. From a translational perspective, elevated expression of Twist1 is also detected in cancer patients with severe muscle wasting, implicating a role of Twist1 in cancer cachexia, and further providing a possible target for therapeutic attenuation of cachexia to improve cancer patient survival. In this article, we will briefly summarize how Twist1 acts as a master regulator of tumor-induced cachexia, and discuss the relevance of our findings to muscle wasting diseases in general. The mechanism of decreased muscle mass in various catabolic conditions is thought to rely on similar pathways, and, therefore, Twist1-induced cancer cachexia may benefit diverse groups of patients with clinical complications associated with loss of muscle mass and functions, beyond the expected benefits for cancer patients. [ABSTRACT FROM AUTHOR]

Muscle wasting is the hallmark of cancer cachexia and is associated with poor quality of life and increased mortality. Valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, has important biological effects in the treatment of muscular dystrophy. To verify whether VPA could ameliorate muscle wasting induced by cancer cachexia, we explored the role of VPA in two cancer cachectic mouse models [induced by colon-26 (C26) adenocarcinoma or Lewis lung carcinoma (LLC)] and atrophied C2C12 myotubes [induced by C26 cell conditioned medium (CCM) or LLC cell conditioned medium (LCM)]. Our data demonstrated that treatment with VPA increased the mass and cross-sectional area of skeletal muscles in tumorbearing mice. Furthermore, treatment with VPA also increased the diameter of myotubes cultured in conditioned medium. The skeletal muscles in cachectic mice or atrophied myotubes treated with VPA exhibited reduced levels of CCAAT/enhancer binding protein beta (C/EBP), resulting in atrogin1 downregulation and the eventual alleviation of muscle wasting and myotube atrophy. Moreover, atrogin1 promoter activity in myotubes was stimulated by CCM via activating the C/EBP-responsive cis-element and subsequently inhibited by VPA. In contrast to the effect of VPA on the levels of C/EBP, the levels of inactivating forkhead box O3 (FoxO3a) were unaffected. In summary, VPA attenuated muscle wasting and myotube atrophy and reduced C/EBP binding to atrogin1 promoter locus in the myotubes. Our discoveries indicate that HDAC inhibition by VPA might be a promising new approach for the preservation of skeletal muscle in cancer cachexia. [ABSTRACT FROM AUTHOR]

ABSTRACT Introduction: The expression of secreted protein acidic and rich in cysteine (SPARC) in skeletal muscle decreases with age. Here, we examined the role of SPARC in skeletal muscle by reducing its expression. Methods: SPARC expression was suppressed by introducing short interfering RNA (siRNA) into mouse tibialis anterior muscle. Myofiber diameter, atrogin1, and muscle RING-finger protein 1 (MuRF1) expression, and tumor necrosis factor-α (TNFα) and transforming growth factor-β (TGFβ) signaling were then analyzed. Results: Reduced SPARC expression caused decreases in the diameter of myofibers, especially fast-type ones, accompanied by upregulation of atrogin1, but not MuRF1, at 10 days after siRNA transfection. The expression of TNFα and TGFβ and the phosphorylation status of p38 were not affected by SPARC knockdown, whereas Smad3 phosphorylation was increased at 2 days after siRNA transfection. Conclusions: The loss of SPARC not only upregulates atrogin1 expression but also enhances TGFβ signaling, which may in turn cause muscle atrophy. Muscle Nerve 48:791-799, 2013 [ABSTRACT FROM AUTHOR]

Abstract: Calcineurn/nuclear factor of the activated T cell (CaN/NFAT) signaling pathway plays crucial roles in the development of cardiac hypertrophy, Down''s syndrome, and autoimmune diseases in response to pathological stimuli. The aim of the present study is to get a system-level understanding on the regulatory mechanism of CaN/NFAT signaling pathway in consideration of the controversial roles of myocyte-enriched calcineurin interacting protein1 (MCIP1) for varying stress stimuli. To this end, we have developed an experimentally validated mathematical model and carried out computer simulations as well as cell-based experiments. Quantitative overexpression and knock-down experiments in C2C12 myoblasts have revealed that MCIP1 functions only as a calcineurin inhibitor. We have also observed a biphasic response of the NFAT activity with increasing stimuli of isoproterenol. Through extensive in silico simulations, we have discovered that the NFAT activity is primarily modulated by ERK5 and MCIP1 under mild isoproterenol stimuli whereas it is mainly modulated by atrogin1 (muscle atrophy F-box protein) under strong isoproterenol stimuli. This study shows that a system-level analysis may help understanding CaN/NFAT signaling-associated disease. [Copyright &y& Elsevier]

Abstract: While the role of the ubiquitin–proteasome system (UPS) in regulating cellular processes continues to expand, the elucidation of its role in cardiac disease is just beginning. The UPS regulates pivotal processes at all levels of cardiac biology: from membrane-associated ion channels and receptors to downstream signaling intermediates and transcription factors. Moreover, the role of the UPS in maintaining cardiac protein quality control is emerging, as exemplified by its multiple interactions with the cardiac sarcomere and role in familial cardiomyopathies. The diversity of UPS regulation lies in E3 ligases, which specifically recognize targets and direct the ubiquitination process. In the context of disease, E3 ligase expression affects the severity of disease in both ischemia reperfusion injury and cardiac hypertrophy in vivo by modulating signaling intermediates. In ischemia–reperfusion injury, the activities of CHIP and MDM2 (both with E3 ligase activity) profoundly affect apoptosis regulation and severity of disease. In cardiac hypertrophy, Atrogin1 and MuRF1 attenuate cardiac hypertrophy by interacting with calcineurin and PKCε, respectively. Additionally, MuRF1 and MDM2 interact with sarcomeric proteins (cTnI and Tcap, respectively) which may prove to be mechanisms by which hypertrophy is attenuated or protein quality modulated. All of these exciting new findings, however, must be taken in the context of disease regulation of the UPS components themselves. Key UPS components (e.g. ubiquitin, E1, E2, E3, proteasome) are themselves transcriptionally regulated in cardiac disease. Our understanding of the precise nature by which the UPS regulates key biological functions in cardiac disease has just begun. [Copyright &y& Elsevier]

Mountain ginseng (Panax ginseng C.A. Meyer) is a medicinal herb with immune effects, muscle damage protection and energy metabolism effects. However, the pharmacological role of mountain ginseng in dexamethasone (DEXA)-induced muscle atrophy through the forkhead box O (FOXO) family is not understood. Therefore, we hypothesized that mountain ginseng inhibits skeletal muscle atrophy by decreasing muscle RING finger protein-1 (MuRF1) and atrogin1 through FOXO3 in L6 myotubes. Rat myoblast (L6) cells or Sprague-Dawley (SD) rats were exposed to DEXA and mountain ginseng. The expressions of muscle atrophy targets such as MuRF1, atrogin1, MyHC (myosin heavy chain), HSP90, p-Akt, Akt, p-ERK1/2, ERK, FOXO3a, FOXO1, myostatin, and follistatin were analyzed by using Western blot analysis or real-time PCR. The diameter of myotubes was measured. Recruitment of glucocorticoid receptor (GR) or FOXO3a was analyzed by performing a chromatin immunoprecipitation (ChIP) assay. Mountain ginseng treatment reduced muscle weight loss and collagen deposition in DEXA-induced rats. Mountain ginseng treatment led to decreases in MuRF1, atrogin1, p-ERK1/2, FOXO3a, FOXO1, and myostatin. Also, mountain ginseng treatment led to increases in the diameter of myotubes, MyHC, HSP90, p-Akt, and follistatin. Treatment with mountain ginseng reduced enrichment of GR, FOXO3a, and RNA polymerase II on the promoters. These results suggest that mountain ginseng inhibits skeletal muscle atrophy by decreasing MuRF1 and atrogin1 through FOXO3a in L6 myotubes. Image 1 • Mountain ginseng increased myotube in skeletal muscle. • Mountain ginseng inhibited MuRF1/atrogin1/FOXO3a/myostatin. [ABSTRACT FROM AUTHOR]

Skeletal muscle atrophy is a common feature of patients suffering with chronic infection and other systemic diseases, including acquired immunodeficiency syndrome, chronic kidney disease and cancer. Therefore, understanding the molecular basis of muscle loss is of importance. The majority of members of the forkhead box O (FoxO) family can induce skeletal muscle atrophy; however, the effect of FoxO6 on skeletal muscle is not completely understood. The present study investigated the role of FoxO6 in vitro and in vivo . Compared with the small interfering RNA (si)‑negative control (NC) group, C 2 C 12 cell proliferation (Cell Counting Kit‑8 assay), myotube differentiation and myotube production were significantly decreased by FoxO6 knockdown, which was different from the known functions of other FoxO members. The immunofluorescence assay results demonstrated that si‑FoxO6 clearly downregulated the expression levels of myosin heavy chain (MyHC) in C 2 C 12 myotubes compared with si‑NC. The western blotting results indicated that compared with the si‑NC group, FoxO6 knockdown induced C 2 C 12 myotube atrophy by notably downregulating myoblast determination protein 1 (MyoD), mTOR and MyHC expression levels, and by markedly upregulating ubiquitin ligase (atrogin1) and muscle RING‑finger protein‑1 (MURF1) expression levels. Similarly, in an in vitro model of TNF‑α‑induced myotube atrophy, the western blotting results indicated that FoxO6 expression levels were decreased, whereas atrogin1, MURF1, FoxO1 and FoxO3a expression levels were increased compared with the control group. Therefore, the results indicated that, unlike FoxO1 or FoxO3a, FoxO6 maintained C 2 C 12 myotubes and protected against atrophy. Consistent with the in vitro data, similar results were observed in vivo . Collectively, the results of the present study suggested that FoxO6 served a critical role in muscle cell metabolism in vitro and in vivo , and might serve as a promising therapeutic target for ameliorating skeletal muscle atrophy.

Background: Atrogin1, which is one of the key genes for the promotion of muscle atrophy, exhibits day-night variation. However, its mechanism and the role of its day-night variation are largely unknown in a muscle atrophic context., Methods: The mice were induced a muscle atrophy by hindlimb-unloading (HU). To examine a role of circadian clock, Wild-type (WT) and Clock mutant mice were used. To test the effects of a neuronal effects, an unilateral ablation of sciatic nerve was performed in HU mice. To test a timing-dependent effects of weight-bearing, mice were released from HU for 4 h in a day at early or late active phase (W-EAP and W-LAP groups, respectively)., Findings: We found that the day-night oscillation of Atrogin1 expression was not observed in Clock mutant mice or in the sciatic denervated muscle. In addition, the therapeutic effects of weight-bearing were dependent on its timing with a better effect in the early active phase., Interpretation: These findings suggest that the circadian clock controls the day-night oscillation of Atrogin1 expression and the therapeutic effects of weight-bearing are dependent on its timing. FUND: Council for Science, Technology, and Innovation, SIP, "Technologies for creating next-generation agriculture, forestry, and fisheries"., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Muscle wasting is the hallmark of cancer cachexia and is associated with poor quality of life and increased mortality. Valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, has important biological effects in the treatment of muscular dystrophy. To verify whether VPA could ameliorate muscle wasting induced by cancer cachexia, we explored the role of VPA in two cancer cachectic mouse models [induced by colon-26 (C26) adenocarcinoma or Lewis lung carcinoma (LLC)] and atrophied C2C12 myotubes [induced by C26 cell conditioned medium (CCM) or LLC cell conditioned medium (LCM)]. Our data demonstrated that treatment with VPA increased the mass and cross-sectional area of skeletal muscles in tumor-bearing mice. Furthermore, treatment with VPA also increased the diameter of myotubes cultured in conditioned medium. The skeletal muscles in cachectic mice or atrophied myotubes treated with VPA exhibited reduced levels of CCAAT/enhancer binding protein beta (C/EBPβ), resulting in atrogin1 downregulation and the eventual alleviation of muscle wasting and myotube atrophy. Moreover, atrogin1 promoter activity in myotubes was stimulated by CCM via activating the C/EBPβ-responsive cis-element and subsequently inhibited by VPA. In contrast to the effect of VPA on the levels of C/EBPβ, the levels of inactivating forkhead box O3 (FoxO3a) were unaffected. In summary, VPA attenuated muscle wasting and myotube atrophy and reduced C/EBPβ binding to atrogin1 promoter locus in the myotubes. Our discoveries indicate that HDAC inhibition by VPA might be a promising new approach for the preservation of skeletal muscle in cancer cachexia., (Copyright © 2016 the American Physiological Society.)