curcumin and Muscular-Atrophy

Sarcopenia is the progressive loss of muscle mass, strength, and functions as we age. The pathogenesis of sarcopenia is underlined by oxidative stress and inflammation. As such, it is reasonable to suggest that a natural compound with both antioxidant and anti-inflammatory activities could prevent sarcopenia. Curcumin, a natural compound derived from turmeric with both properties, could benefit muscle health. This review aims to summarise the therapeutic effects of curcumin on cellular, animal, and human studies. The available evidence found in the literature showed that curcumin prevents muscle degeneration by upregulating the expression of genes related to protein synthesis and suppressing genes related to muscle degradation. It also protects muscle health by maintaining satellite cell number and function, protecting the mitochondrial function of muscle cells, and suppressing inflammation and oxidative stress. However, it is noted that most studies are preclinical. Evidence from randomised control trials in humans is lacking. In conclusion, curcumin has the potential to be utilised to manage muscle wasting and injury, pending more evidence from carefully planned human clinical trials.

Topics: Aging; Animals; Curcumin; Humans; Inflammation; Muscle, Skeletal; Muscular Atrophy; Oxidative Stress; Sarcopenia

To highlight recent evidence for the ability of polyphenols and their derivatives to reduce muscle wasting in different pathological states.. From January 2016 to August 2017, four articles dealt with the effects of polyphenols on muscle wasting, which were all carried out in mice. The four studies found that polyphenols reduced muscle mass loss associated with cancer cachexia, acute inflammation or sciatic nerve section. One study even showed that muscle mass was totally preserved when rutin was added to the diet of mice undergoing cancer cachexia. The beneficial effects of polyphenols on muscle wasting were mainly due to a reduction in the activation of the nuclear factor-kappa B pathway, a lower oxidative stress level and a better mitochondrial function. In addition, urolithin B was found to have a testosterone-like effect and to favorably regulate muscle protein balance.. During the last 20 months, additional data have been collected about the beneficial effects of rutin, curcumin, quercetin, ellagitanins and urolithin B to limit the loss of muscle mass associated with several pathological states. However, currently, scientific evidence lacks for their use as nutraceuticals in human.

Topics: Animals; Cachexia; Coumarins; Curcumin; Humans; Hydrolyzable Tannins; Mitochondria; Muscle, Skeletal; Muscular Atrophy; NF-kappa B; Oxidative Stress; Phytotherapy; Plant Extracts; Polyphenols; Quercetin; Rutin; Wasting Syndrome

The Indian spice turmeric, in which the active and dominant biomolecule is curcumin, has been demonstrated to have significant medicinal properties, including anti-inflammatory and anti-neoplastic effects. This promise is potentially very applicable to musculoskeletal disorders, which are common causes of physician visits worldwide. Research at the laboratory, translational and clinical levels that supports the use of curcumin for various musculoskeletal disorders, such as osteoarthritis, osteoporosis, musculocartilaginous disorders, and sarcoma is here in comprehensively summarized. Though more phase I-III trials are clearly needed, thus far the existing data show that curcumin can indeed potentially be useful in treatment of the hundreds of millions worldwide who are afflicted by these musculoskeletal disorders.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Bone Density Conservation Agents; Cartilage Diseases; Curcumin; Humans; Muscular Atrophy; Musculoskeletal Diseases; Osteoarthritis; Osteoporosis; Sarcoma; Translational Research, Biomedical

Sepsis, severe injury, and cancer are associated with loss of muscle mass. Muscle wasting in these conditions is mainly caused by increased proteolysis, at least in part regulated by nuclear factor-kappaB. Despite recent progress in the understanding of mediators and mechanisms involved in muscle wasting, effective and universally accepted treatments by which muscle atrophy can be prevented or reversed are still lacking. We review recent evidence suggesting that curcumin (diferuloylmethane), a component of the spice turmeric, may prevent loss of muscle mass during sepsis and endotoxemia and may stimulate muscle regeneration after traumatic injury. Curcumin has been part of the traditional Asian medicine for centuries, mainly because of its anti-inflammatory properties. Studies suggest that inhibition of nuclear factor-kappaB is one of the mechanisms by which curcumin exerts its ant-inflammatory effects. Curcumin is easily accessible, inexpensive, and non-toxic even at high doses, and may therefore offer an important treatment modality in muscle wasting and injury. It should be noted, however, that the muscle-sparing effects of curcumin are not universally accepted, and more studies are therefore needed to further test the role of curcumin in the prevention and treatment of muscle wasting.

Topics: Animals; Curcumin; Humans; Muscle Proteins; Muscle, Skeletal; Muscular Atrophy; NF-kappa B; Regeneration; Wounds and Injuries

Curcumin is a polyphenol plant-derived compound with anti-inflammatory, antioxidant stress, and anticancer properties that make it have the potential to treat cancer cachexia. However, the role of it in breast cancer cachexia remains unclear.. The 4T1 cells were subcutaneously injected into BALB/c mice to induce breast cancer cachexia. After tumor formation, the animals were divided into groups and given curcumin or saline interventions. The therapeutic effect of curcumin on breast cancer cachexia was characterized by tumor growth, changes in body mass and gastrocnemius mass, muscle function test, histopathology, and serum nutrition indexes. Mitochondrial function in muscle tissue was observed by transmission electron microscopy and ATP detection, muscle inflammatory factors were detected by ELISA, muscle differential metabolites were detected by. Dynamic. Curcumin reduces ubiquitination, inflammation in skeletal muscle by regulating the NF-KB/UPS axis and improves muscle malignant metabolic phenotype and mitochondrial dysfunction, to alleviate muscle atrophy and loss of function in mice with breast cancer cachexia.

Topics: Animals; Cachexia; Curcumin; Humans; Mice; Mice, Inbred BALB C; Muscle, Skeletal; Muscular Atrophy; NF-kappa B; Proteasome Endopeptidase Complex; Triple Negative Breast Neoplasms; Ubiquitin

Sarcopenia is the decline in skeletal muscle mass, strength, and functions, which decreases the quality of life in elderly people. This study investigated the suppressive effect of turmeric (Curcuma longa) extract (TE) on muscle atrophy in dexamethasone (DEX)-treated mice and C2C12 myotubes. DEX treatment significantly decreased the muscle weight and significantly increased Fbxo32 and Murf1 expression in mice, and these changes were suppressed by the supplementation of an AIN-93 based diet with 2% TE. A similar pattern was observed in FBXO32 and MuRF1 protein expression. In C2C12 myotubes, DEX treatment significantly increased FBXO32 and MuRF1 gene and protein expression, and these increases were significantly suppressed by TE supplementation at a concentration of 200 µg/mL. Furthermore, one of the five TE fractions, which were separated by high-performance liquid chromatography had a similar effect with TE supplementation. The present study proposes the suppressive effect of turmeric on sarcopenia.

Topics: Animals; Curcuma; Dexamethasone; Mice; Muscle Fibers, Skeletal; Muscle, Skeletal; Muscular Atrophy; Plant Extracts; Quality of Life; Sarcopenia; Ubiquitin-Protein Ligases

Muscle wasting and cachexia are prominent comorbidities in cancer. Treatment with polyphenolic compounds may partly revert muscle wasting. We hypothesized that treatment with curcumin or resveratrol in cancer cachectic mice may improve muscle phenotype and total body weight through attenuation of several proteolytic and signaling mechanisms in limb muscles. In gastrocnemius and soleus muscles of cancer cachectic mice (LP07 adenocarcinoma cells, N = 10/group): (1) LC-induced cachexia, (2) LC-cachexia+curcumin, and (3) LC-cachexia + resveratrol, muscle structure and damage (including blood troponin I), sirtuin-1, proteolytic markers, and signaling pathways (NF-κB and FoxO3) were explored (immunohistochemistry and immunoblotting). Compared to nontreated cachectic mice, in LC-cachexia + curcumin and LC-cachexia + resveratrol groups, body and muscle weights (gastrocnemius), limb muscle strength, muscle damage, and myofiber cross-sectional area improved, and in both muscles, sirtuin-1 increased, while proteolysis (troponin I), proteolytic markers, and signaling pathways were attenuated. Curcumin and resveratrol elicited beneficial effects on fast- and slow-twitch limb muscle phenotypes in cachectic mice through sirtuin-1 activation, attenuation of atrophy signaling pathways, and proteolysis in cancer cachectic mice. These findings have future therapeutic implications as these natural compounds, separately or in combination, may be used in clinical settings of muscle mass loss and dysfunction including cancer cachexia.

Topics: Animals; Biomarkers; Cachexia; Cell Line; Curcumin; Female; Mice, Inbred BALB C; Muscle Proteins; Muscles; Muscular Atrophy; Neoplasms; Phenotype; Proteolysis; Resveratrol; Signal Transduction; Sirtuin 1

Topics: Animals; Curcumin; Hindlimb Suspension; Muscle, Skeletal; Muscular Atrophy; Phenotype; Proteolysis; Signal Transduction

Chronic hypobaric hypoxia induced muscle atrophy results in decreased physical performance at high altitude. Curcumin has been shown to have muscle sparing effects under cachectic conditions. However, the protective effects of curcumin under chronic hypobaric hypoxia have not been studied till now. Therefore, the present study aims at evaluating the effects of curcumin administration on muscle atrophy under chronic hypobaric hypoxia. Male Sprague Dawley rats were divided into four groups: Control (C)-normoxia exposed, Control Treated (CT)-normoxia exposed and administered with curcumin at a dose of 100 mg/kg body weight for 14 days, Hypoxia (H)-exposed to hypobaric hypoxia for 14 days and Hypoxia Treated (HT)-exposed to hypobaric hypoxia and administered with curcumin for 14 days. Oxidative stress, muscle protein degradation, proteolytic pathways, myosin heavy chain (MHC), CPK activity and muscle histology were performed in gastrocnemius muscle samples of the exposed rats. In addition, fatigue time on treadmill running was also evaluated to observe the effects of curcumin administration on physical performance of the rats. As previously shown, hypobaric hypoxia increased muscle protein degradation via upregulated calpain and ubiquitin-proteolytic pathways. An enhanced oxidative stress has been linked to upregulation of these pathways under hypoxic conditions. Curcumin administration resulted in reduced oxidative stress as well as reduced activity of the proteolytic pathways in HT group as compared to H group thereby resulting in reduced muscle protein degradation under hypobaric hypoxia. Histology of rat muscle revealed an increased number of muscle fibres in HT as compared to H group. Thus, increased number of muscle fibres and decreased muscle proteolysis following curcumin administration, lead to enhanced muscle mass under hypobaric hypoxia resulting in improved physical performance of the rats.

Topics: Altitude; Altitude Sickness; Animals; Curcumin; Hypoxia; Male; Muscular Atrophy; Rats; Rats, Sprague-Dawley

Skeletal muscle is a highly adaptable tissue capable of remodeling when dynamic stress is altered, including changes in mechanical loading and stretch. When muscle is subjected to an unloaded state (e.g., bedrest, immobilization, spaceflight) the resulting loss of muscle cross sectional area (CSA) impairs force production. In addition, muscle fiber-type shifts from slow to fast-twitch fibers. Unloading also results in a downregulation of heat shock proteins (e.g., HSP70) and anabolic signaling, which further exacerbate these morphological changes. Our lab recently showed reactive oxygen species (ROS) are causal in unloading-induced alterations in Akt and FoxO3a phosphorylation, muscle fiber atrophy, and fiber-type shift. Nutritional supplements such as fish oil and curcumin enhance anabolic signaling, glutathione levels, and heat shock proteins. We hypothesized that fish oil, rich in omega-3-fatty acids, combined with the polyphenol curcumin would enhance stress protective proteins and anabolic signaling in the rat soleus muscle, concomitant with synergistic protection of morphology. C57BL/6 mice were assigned to 3 groups (n = 6/group): ambulatory controls (CON), hindlimb unloading (HU), and hindlimb unloading with 5% fish oil, 1% curcumin in diet (FOC). FOC treatments began 10 days prior to HU and tissues were harvested following 7 days of HU. FOC mitigated the unloading induced decrease in CSA. FOC also enhanced abundance of HSP70 and anabolic signaling (Akt phosphorylation, p70S6K phosphorylation), while reducing Nox2, a source of oxidative stress. Therefore, we concluded that the combination of fish oil and curcumin prevents skeletal muscle atrophy due to a boost of heat shock proteins and anabolic signaling in an unloaded state.

Topics: Anabolic Agents; Animals; Antioxidants; Curcuma; Curcumin; Drug Therapy, Combination; Fish Oils; Heat-Shock Proteins; Hindlimb Suspension; HSP70 Heat-Shock Proteins; Male; Mice, Inbred C57BL; Muscle Fibers, Skeletal; Muscle Proteins; Muscle, Skeletal; Muscular Atrophy; NADPH Oxidase 2; Oxidative Stress; Phosphorylation; Plant Extracts; Proto-Oncogene Proteins c-akt; Rats; Ribosomal Protein S6 Kinases, 70-kDa

Standard in vitro myotube culture conditions are nonphysiological and there is increasing evidence that this may distort adaptations to both catabolic and anabolic stimuli and hamper preclinical research into mechanisms and treatments for muscle atrophy in cancer and other chronic diseases. We tested a new model of myotube culture which mimics more accurately the basal conditions for muscle tissue in patients with chronic disease, such as cancer. Myotubes derived from C2C12 myoblasts, cultured under the modified conditions were thinner, more numerous, with more uniform morphology and an increased proportion of mature myotubes. Furthermore, modified conditions led to increased expression of mir-210-3p, genes related to slow-twitch, oxidative phenotype and resistance to commonly used experimental atrophy-inducing treatments. However, treatment with a combination of drugs used in anti-cancer treatment (doxorubicin and dexamethasone) under the modified culture conditions did lead to myotube atrophy which was only partially prevented by co-administration of curcumin. The results underline the importance and potential advantages of using physiological conditions for in vivo experiments investigating mechanisms of muscle atrophy and especially for preclinical screening of therapies for cancer-related muscle wasting.

Topics: Animals; Antibiotics, Antineoplastic; Cell Culture Techniques; Cells, Cultured; Curcumin; Dexamethasone; Doxorubicin; Gene Expression Regulation; Mice; MicroRNAs; Muscle Fibers, Skeletal; Muscle Proteins; Muscular Atrophy

EPA has been clinically shown to reduce muscle wasting during cancer cachexia. This study investigates whether curcumin or green tea extract (GTE) enhances the ability of low doses of eicosapentaenoic acid (EPA) to reduce loss of muscle protein in an in vitro model. A low dose of EPA with minimal anti-cachectic activity was chosen to evaluate any potential synergistic effect with curcumin or GTE. Depression of protein synthesis and increase in degradation was determined in C2C12 myotubes in response to tumour necrosis factor-α (TNF-α) and proteolysis-inducing factor (PIF). EPA (50 μM) or curcumin (10 μg ml(-1)) alone had little effect on protein degradation caused by PIF but the combination produced complete inhibition, as did the combination with GTE (10 μg ml(-1)). In response to TNF-α (25 ng ml(-1))-induced protein degradation, EPA had a small, but not significant effect on protein degradation; however, when curcumin and GTE were combined with EPA, the effect was enhanced. EPA completely attenuated the depression of protein synthesis caused by TNF-α, but not that caused by PIF. The combination of EPA with curcumin produced a significant increase in protein synthesis to both agents. GTE alone or in combination with EPA had no effect on the depression of protein synthesis by TNF-α, but did significantly increase protein synthesis in PIF-treated cells. Both TNF-α and PIF significantly reduced myotube diameter from 17 to 13 μm for TNF-α (23.5%) and 15 μm (11.8%) for PIF However the triple combination of EPA, curcumin and GTE returned diameters to values not significantly different from the control. These results suggest that either curcumin or GTE or the combination could enhance the anti-catabolic effect of EPA on lean body mass.

Topics: Animals; Curcumin; Eicosapentaenoic Acid; Humans; Mice; Muscle Fibers, Skeletal; Muscle, Skeletal; Muscular Atrophy; Plant Extracts; Proteoglycans; Proteolysis; Tea; Tumor Necrosis Factor-alpha

The electrical current exclusion (ECE) principle provides an alternative to common methods of cell diameter measurement and especially in atrophy and cancer associated cachexia research. C2C12 myoblasts were differentiated into myotubes and treated with 100 μM dexamethasone to induce atrophy in vitro. Subsequently, they were incubated for 24 h with media containing different concentrations of curcumin and/or branched-chain amino acids (BCAAs) in order to counteract atrophy. After treatment with curcumin, an increase in cell diameter was detectable; the highest increase with 13.9 ± 0.4% was seen with 10 μM curcumin. The combination of curcumin and BCAAs showed an increase of 13.4 ± 1.2 %. Cell diameter measurement via the ECE showed that curcumin, and curcumin in combination with BCAAs, were able to restore atrophic C2C12 myotubes. Therefore, the application of ECE in muscle atrophy and also cancer-associated cachexia research allows rapid screening of novel compounds in order to test their efficacy in vitro.

Topics: Cachexia; Cell Differentiation; Cell Line; Curcumin; Dexamethasone; Humans; Muscle Fibers, Skeletal; Muscle Proteins; Muscular Atrophy; Myoblasts; Neoplasms

What is the central question of this study? We sought to examine whether curcumin could ameliorate skeletal muscle atrophy in diabetic mice by inhibiting protein ubiquitination, inflammatory cytokines and oxidative stress. What is the main finding and its importance? We found that curcumin ameliorated skeletal muscle atrophy in streptozotocin-induced diabetic mice by inhibiting protein ubiquitination without affecting protein synthesis. This favourable effect of curcumin was possibly due to the inhibition of inflammatory cytokines and oxidative stress. Curcumin may be beneficial for the treatment of muscle atrophy in type 1 diabetes mellitus. Skeletal muscle atrophy develops in patients with diabetes mellitus (DM), especially in type 1 DM, which is associated with chronic inflammation. Curcumin, the active ingredient of turmeric, has various biological actions, including anti-inflammatory and antioxidant properties. We hypothesized that curcumin could ameliorate skeletal muscle atrophy in mice with streptozotocin-induced type 1 DM. C57BL/6 J mice were injected with streptozotocin (200 mg kg(-1) i.p.; DM group) or vehicle (control group). Each group of mice was randomly subdivided into two groups of 10 mice each and fed a diet with or without curcumin (1500 mg kg(-1) day(-1)) for 2 weeks. There were significant decreases in body weight, skeletal muscle weight and cellular cross-sectional area of the skeletal muscle in DM mice compared with control mice, and these changes were significantly attenuated in DM+Curcumin mice without affecting plasma glucose and insulin concentrations. Ubiquitination of protein was increased in skeletal muscle from DM mice and decreased in DM+Curcumin mice. Gene expressions of muscle-specific ubiquitin E3 ligase atrogin-1/MAFbx and MuRF1 were increased in DM and inhibited in DM+Curcumin mice. Moreover, nuclear factor-κB activation, concentrations of the inflammatory cytokines tumour necrosis factor-α and interleukin-1β and oxidative stress were increased in the skeletal muscle from DM mice and inhibited in DM+Curcumin mice. Curcumin ameliorated skeletal muscle atrophy in DM mice by inhibiting protein ubiquitination, inflammatory cytokines and oxidative stress. Curcumin may be beneficial for the treatment of muscle atrophy in type 1 DM.

Topics: Animals; Antioxidants; Body Weight; Curcumin; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Gene Expression; Insulin; Interleukin-1beta; Male; Mice; Mice, Inbred C57BL; Muscle Proteins; Muscle, Skeletal; Muscular Atrophy; NF-kappa B; Oxidative Stress; Signal Transduction; SKP Cullin F-Box Protein Ligases; Tripartite Motif Proteins; Tumor Necrosis Factor-alpha; Ubiquitin-Protein Ligases; Ubiquitination

Antioxidant administration aimed to antagonize the development and progression of disuse muscle atrophy provided controversial results. Here we investigated the effects of curcumin, a vegetal polyphenol with pleiotropic biological activity, because of its ability to upregulate glucose-regulated protein 94 kDa (Grp94) expression in myogenic cells. Grp94 is a sarco-endoplasmic reticulum chaperone, the levels of which decrease significantly in unloaded muscle. Rats were injected intraperitoneally with curcumin and soleus muscle was analysed after 7 days of hindlimb unloading or standard caging. Curcumin administration increased Grp94 protein levels about twofold in muscles of ambulatory rats (P < 0.05) and antagonized its decrease in unloaded ones. Treatment countered loss of soleus mass and myofibre cross-sectional area by approximately 30% (P ≤ 0.02) and maintained a force-frequency relationship closer to ambulatory levels. Indexes of muscle protein and lipid oxidation, such as protein carbonylation, revealed by Oxyblot, and malondialdehyde, measured with HPLC, were significantly blunted in unloaded treated rats compared to untreated ones (P = 0.01). Mechanistic involvement of Grp94 was suggested by the disruption of curcumin-induced attenuation of myofibre atrophy after transfection with antisense grp94 cDNA and by the drug-positive effect on the maintenance of the subsarcolemmal localization of active neuronal nitric oxide synthase molecules, which were displaced to the sarcoplasm by unloading. The absence of additive effects after combined administration of a neuronal nitric oxide synthase inhibitor further supported curcumin interference with this pro-atrophic pathway. In conclusion, curcumin represents an effective and safe tool to upregulate Grp94 muscle levels and to maintain muscle function during unweighting.

Topics: Animals; Antioxidants; Curcumin; Female; Hindlimb Suspension; Membrane Glycoproteins; Muscle, Skeletal; Muscular Atrophy; Nitric Oxide Synthase Type I; Rats, Wistar; Sarcolemma

Immobilization is characterized by activation of the ubiquitin (Ub)-proteasome-dependent proteolytic system (UPS) and of the mitochondrial apoptotic pathway. Increased oxidative stress and inflammatory response occur in immobilized skeletal muscles. Curcumin exhibits antioxidant and anti-inflammatory properties, blocked proteasome activation in intact animals, and may favor skeletal muscle regeneration. We therefore measured the effects of curcumin on immobilization-induced muscle atrophy and subsequent recovery. Rats were subjected to hindlimb immobilization for 8 days (I8) and allowed to recover for 10 days (R10). Fifty percent of the rats were injected daily with either curcumin or vehicle. Proteolytic and apoptotic pathways were studied in gastrocnemius muscles. Curcumin treatment prevented the enhanced proteasome chymotrypsin-like activity and the trend toward increased caspase-9-associated apoptosome activity at I8 in immobilized muscles. By contrast, the increase of these two activities was blunted by curcumin at R10. Curcumin did not reduce muscle atrophy at I8 but improved muscle recovery at R10 and the cross-sectional area of muscle fibers of immobilized muscles. Curcumin reduced the increased protein levels of Smac/DIABLO induced by immobilization and enhanced the elevation of X-linked inhibitory apoptotic protein levels at R10. Ub-conjugate levels and caspase-3 activity increased at I8 and were normalized at R10 without being affected by curcumin treatment. Altogether, the data show that curcumin treatment improved recovery during reloading. The effect of curcumin during the atrophic phase on proteasome activities may facilitate the initiation of muscle recovery after reloading. These data also suggest that this compound may favor the initial steps of muscle regeneration.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Apoptosis; Apoptosomes; Caspase 3; Caspase 9; Curcumin; Hindlimb Suspension; Male; Mitochondria; Muscle Proteins; Muscle, Skeletal; Muscular Atrophy; Plant Extracts; Proteasome Endopeptidase Complex; Rats; Rats, Wistar; Regeneration; Up-Regulation

Muscle wasting or cachexia is caused by accelerated muscle protein breakdown via the ubiquitin-proteasome complex. We investigated the effect of curcumin c3 complex (curcumin c3) on attenuation of muscle proteolysis using in vitro and in vivo models. Our in vitro data indicate that curcumin c3 as low as 0.50 microg/ml was very effective in significantly inhibiting (30 %; P < 0.05) tyrosine release from human skeletal muscle cells, which reached a maximum level of inhibition of 60 % (P < 0.05) at 2.5 microg/ml. Curcumin c3 at 2.5 microg/ml also inhibited chymotrypsin-like 20S proteasome activity in these cells by 25 % (P < 0.05). For in vivo studies, we induced progressive muscle wasting in mice by implanting the MAC16 colon tumour. The in vivo data indicate that low doses of curcumin c3 (100 mg/kg body weight) was able to prevent weight loss in mice bearing MAC16 tumours whereas higher doses of curcumin c3 (250 mg/kg body weight) resulted in approximately 25 % (P < 0.05) weight gain as compared with the placebo-treated animals. Additionally, the effect of curcumin c3 on preventing and/or reversing cachexia was also evident by gains in the weight of the gastrocnemius muscle (30-58 %; P < 0.05) and with the increased size of the muscle fibres (30-65 %; P < 0.05). Furthermore, curcumin inhibited proteasome complex activity and variably reduced expression of muscle-specific ubiquitin ligases: atrogin-1/muscle atrophy F-box (MAFbx) and muscle RING finger 1 (MURF-1). In conclusion, oral curcumin c3 results in the prevention and reversal of weight loss. The data imply that curcumin c3 may be an effective adjuvant therapy against cachexia.

Topics: Animals; Cachexia; Cells, Cultured; Colonic Neoplasms; Curcumin; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Humans; Mice; Muscle Fibers, Skeletal; Muscle Proteins; Muscle, Skeletal; Muscular Atrophy; Myoblasts; Proteasome Endopeptidase Complex; Weight Loss; Xenograft Model Antitumor Assays

Because elevated ubiquitin ligase atrogin-1/MAFbx and MuRF1 mediate skeletal muscle wasting associated with various catabolic conditions, the signaling pathways involved in the upregulation of these genes under pathological conditions are considered therapeutic targets. AKT and NF-kappaB have been previously shown to regulate the expression of atrogin-1/MAFbx or MuRF1, respectively. In addition, we recently found that p38 MAPK mediates TNF-alpha upregulation of atrogin-1/MAFbx expression, suggesting that multiple signaling pathways mediate muscle wasting in inflammatory diseases. To date, however, these advances have not resulted in a practical clinical intervention for disease-induced muscle wasting. In the present study, we tested the effect of curcumin--a non-toxic anti-inflammatory reagent that inhibits p38 and NF-kappaB--on lipopolysaccharide (LPS)-induced muscle wasting in mice. Daily intraperitoneal (i.p.) injection of curcumin (10-60 micro g/kg) for 4 days inhibited, in a dose-dependent manner, the LPS-stimulated (1 mg/kg, i.p.) increase of atrogin-1/MAFbx expression in gastrocnemius and extensor digitorum longus (EDL) muscles, resulting in the attenuation of muscle protein loss. It should also be noted that curcumin administration did not alter the basal expression of atrogin-1/MAFbx, nor did it affect LPS-stimulated MuRF1 and polyubiquitin expression. LPS activated p38 and NF-kappaB, while inhibiting AKT; whereas, curcumin administration inhibited LPS-stimulated p38 activation, without altering the effect of LPS on NF-kappaB and AKT. These results indicate that curcumin is effective in blocking LPS-induced loss of muscle mass through the inhibition of p38-mediated upregulation of atrogin-1/MAFbx.

Topics: Animals; Blotting, Northern; Blotting, Western; Curcumin; Dose-Response Relationship, Drug; Electrophoretic Mobility Shift Assay; Gene Expression Regulation; Lipopolysaccharides; Male; Mice; Mice, Inbred ICR; Muscle Proteins; Muscular Atrophy; NF-kappa B; p38 Mitogen-Activated Protein Kinases; Signal Transduction; SKP Cullin F-Box Protein Ligases; Ubiquitin; Up-Regulation

Skeletal muscle of patients with Duchenne-type muscular dystrophy and mdx mice exhibits elevated activity of the transcription factor NF-kappaB (nuclear factor-kappaB), which may play a role in muscle catabolism. We measured skeletal muscle NF-kappaB activity in mdx mice at three ages (10 days, 4 weeks, and 8 weeks) to test the hypothesis that NF-kappaB activity is elevated in an age-dependent manner in these mice. In addition, we tested the hypothesis that NF-kappaB activity could be reduced in mdx skeletal muscle by dietary supplementation with curcumin (1% w/v) or by fatiguing muscle contractions. We found that NF-kappaB activity was elevated at 4 and 8 weeks of age but not at 10 days, and was resistant to inhibition by either fatiguing contractions or dietary curcumin. We conclude that NF-kappaB activity is elevated in dystrophic skeletal muscle in an age-related manner and is resistant to inhibition by physiological and pharmacological means. These findings are consistent with a role for NF-kappaB activation in dystrophic muscle wasting but suggest that predicted interventions such as exercise or inhibitors of the early steps in the NF-kappa activation pathway may not be effective and that targeted research is needed to identify novel therapeutic strategies.

Topics: Animals; Curcumin; Disease Models, Animal; Enzyme Inhibitors; In Vitro Techniques; Mice; Mice, Inbred C57BL; Mice, Inbred mdx; Muscle Contraction; Muscular Atrophy; Muscular Dystrophy, Animal; Muscular Dystrophy, Duchenne; NF-kappa B