Valproic acid attenuates skeletal muscle wasting by inhibiting C/EBPβ-regulated atrogin1 expression in cancer cachexia

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.

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Myostatin is a novel tumoral factor that induces cancer cachexia

Biochemical Journal ◽

10.1042/bj20112024 ◽

2012 ◽

Vol 446 (1) ◽

pp. 23-36 ◽

Cited By ~ 59

Author(s):

Sudarsanareddy Lokireddy ◽

Isuru Wijerupage Wijesoma ◽

Sabeera Bonala ◽

Meng Wei ◽

Siu Kwan Sze ◽

...

Keyword(s):

Skeletal Muscle ◽

Growth Factor ◽

Skeletal Muscles ◽

Cancer Cachexia ◽

Muscle Wasting ◽

Transforming Growth Factor ◽

C2c12 Myotubes ◽

E3 Ligases ◽

Molecular Features ◽

Skeletal Muscle Wasting

Humoral and tumoral factors collectively promote cancer-induced skeletal muscle wasting by increasing protein degradation. Although several humoral proteins, namely TNFα (tumour necrosis factor α) and IL (interleukin)-6, have been shown to induce skeletal muscle wasting, there is a lack of information regarding the tumoral factors that contribute to the atrophy of muscle during cancer cachexia. Therefore, in the present study, we have characterized the secretome of C26 colon cancer cells to identify the tumoral factors involved in cancer-induced skeletal muscle wasting. In the present study, we show that myostatin, a procachectic TGFβ (transforming growth factor β) superfamily member, is abundantly secreted by C26 cells. Consistent with myostatin signalling during cachexia, treating differentiated C2C12 myotubes with C26 CM (conditioned medium) resulted in myotubular atrophy due to the up-regulation of muscle-specific E3 ligases, atrogin-1 and MuRF1 (muscle RING-finger protein 1), and enhanced activity of the ubiquitin–proteasome pathway. Furthermore, the C26 CM also activated ActRIIB (activin receptor type II B)/Smad and NF-κB (nuclear factor κB) signalling, and reduced the activity of the IGF-I (insulin-like growth factor 1)/PI3K (phosphoinositide 3-kinase)/Akt pathway, three salient molecular features of myostatin action in skeletal muscles. Antagonists to myostatin prevented C26 CM-induced wasting in muscle cell cultures, further confirming that tumoral myostatin may be a key contributor in the pathogenesis of cancer cachexia. Finally, we show that treatment with C26 CM induced the autophagy–lysosome pathway and reduced the number of mitochondria in myotubes. These two previously unreported observations were recapitulated in skeletal muscles collected from C26 tumour-bearing mice.

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Change in skeletal muscle index and its prognostic significance in patients who underwent successful conversion therapy for initially unresectable colorectal cancer: observational study

Therapeutic Advances in Gastroenterology ◽

10.1177/1756284820971197 ◽

2020 ◽

Vol 13 ◽

pp. 175628482097119

Author(s):

Hiroaki Nozawa ◽

Shigenobu Emoto ◽

Koji Murono ◽

Yasutaka Shuno ◽

Kazushige Kawai ◽

...

Keyword(s):

Colorectal Cancer ◽

Skeletal Muscle ◽

Systemic Therapy ◽

Skeletal Muscles ◽

Prognostic Significance ◽

Stage Iv ◽

The Body ◽

Conversion Therapy ◽

Cross Sectional ◽

Skeletal Muscle Index

Background: Systemic therapy can cause loss of skeletal muscle mass in colorectal cancer (CRC) patients in the neoadjuvant and palliative settings. However, it is unknown how the body composition is changed by chemotherapy rendering unresectable CRC to resectable disease or how it affects the prognosis. This study aimed at elucidating the effects of systemic therapy on skeletal muscles and survival in stage IV CRC patients who underwent conversion therapy. Methods: We reviewed 98 stage IV CRC patients who received systemic therapy in our hospital. According to the treatment setting, patients were divided into the conversion, neoadjuvant chemotherapy (NAC), and palliation groups. The cross-sectional area of skeletal muscles at the third lumbar level and changes in the skeletal muscle index (SMI), defined as the area divided by height squared, during systemic therapy were compared among patient groups. The effects of these parameters on prognosis were analyzed in the conversion group. Results: The mean SMI increased by 9.4% during systemic therapy in the conversion group ( n = 38), whereas it decreased by 5.9% in the NAC group ( n = 18) and 3.7% in the palliation group ( n = 42, p < 0.0001). Moreover, patients with increased SMI during systemic therapy had a better overall survival (OS) than those whose SMI decreased in the conversion group ( p = 0.025). The increase in SMI was an independent predictor of favorable OS on multivariate analysis (hazard ratio 0.25). Conclusions: Stage IV CRC patients who underwent conversion to resection often had an increased SMI. On the other hand, a decrease in the SMI during systemic therapy was a negative prognostic factor in such patients.

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Atractylenolide III Attenuates Muscle Wasting in Chronic Kidney Disease via the Oxidative Stress-Mediated PI3K/AKT/mTOR Pathway

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/1875471 ◽

2019 ◽

Vol 2019 ◽

pp. 1-16 ◽

Cited By ~ 1

Author(s):

Mingqing Wang ◽

Rong Hu ◽

Yanjing Wang ◽

Lingyu Liu ◽

Haiyan You ◽

...

Keyword(s):

Oxidative Stress ◽

Skeletal Muscle ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Skeletal Muscles ◽

Muscle Wasting ◽

Mtor Pathway ◽

C2c12 Myoblast ◽

Model Group ◽

Atractylenolide Iii

Oxidative stress contributes to muscle wasting in advanced chronic kidney disease (CKD) patients. Atractylenolide III (ATL-III), the major active constituent of Atractylodes rhizome, has been previously reported to function as an antioxidant. This study is aimed at investigating whether ATL-III has protective effects against CKD-induced muscle wasting by alleviating oxidative stress. The results showed that the levels of serum creatinine (SCr), blood urea nitrogen (BUN), and urinary protein significantly decreased in the ATL-III treatment group compared with the 5/6 nephrectomy (5/6 Nx) model group but were higher than those in the sham operation group. Skeletal muscle weight was increased, while inflammation was alleviated in the ATL-III administration group compared with the 5/6 Nx model group. ATL-III-treated rats also showed reduced dilation of the mitochondria, increased CAT, GSH-Px, and SOD activity, and decreased levels of MDA both in skeletal muscles and serum compared with 5/6 Nx model rats, suggesting that ATL-III alleviated mitochondrial damage and increased the activity of antioxidant enzymes, thus reducing the production of ROS. Furthermore, accumulated autophagosomes (APs) and autolysosomes (ALs) were reduced in the gastrocnemius (Gastroc) muscles of ATL-III-treated rats under transmission electron microscopy (TEM) together with the downregulation of LC3-II and upregulation of p62 according to Western blotting. This evidence indicated that ATL-III improved skeletal muscle atrophy and alleviated oxidative stress and autophagy in CKD rats. Furthermore, ATL-III could also increase the protein levels of p-PI3K, p-AKT, and p-mTOR in skeletal muscles in CKD rats. To further reveal the relevant mechanism, the oxidative stress-mediated PI3K/AKT/mTOR pathway was assessed, which showed that a reduced expression of p-PI3K, p-AKT, and p-mTOR in C2C12 myoblast atrophy induced by TNF-α could be upregulated by ATL-III; however, after the overexpression of Nox2 to increase ROS production, the attenuated effect was reversed. Our findings indicated that ATL-III is a potentially protective drug against muscle wasting via activation of the oxidative stress-mediated PI3K/AKT/mTOR pathway.

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Exercise as an anti-inflammatory therapy for cancer cachexia: a focus on interleukin-6 regulation

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00147.2019 ◽

2020 ◽

Vol 318 (2) ◽

pp. R296-R310 ◽

Cited By ~ 7

Author(s):

Hélène N. Daou

Keyword(s):

Skeletal Muscle ◽

Systemic Inflammation ◽

Cancer Cachexia ◽

Muscle Wasting ◽

Skeletal Muscle Atrophy ◽

Ampk Signaling ◽

Skeletal Muscle Wasting ◽

Skeletal Muscle Loss ◽

Anti Inflammatory ◽

Tumor Growth And Metastasis

Cancer cachexia is a complicated disorder of extreme, progressive skeletal muscle wasting. It is directed by metabolic alterations and systemic inflammation dysregulation. Numerous studies have demonstrated that increased systemic inflammation promotes this type of cachexia and have suggested that cytokines are implicated in the skeletal muscle loss. Exercise is firmly established as an anti-inflammatory therapy that can attenuate or even reverse the process of muscle wasting in cancer cachexia. The interleukin IL-6 is generally considered to be a key player in the development of the microenvironment of malignancy; it promotes tumor growth and metastasis by acting as a bridge between chronic inflammation and cancerous tissue and it also induces skeletal muscle atrophy and protein breakdown. Paradoxically, a beneficial role for IL-6 has also been identified recently, and that is its status as a “founding member” of the myokine class of proteins. Skeletal muscle is an important source of circulating IL-6 in people who participate in exercise training. IL-6 acts as an anti-inflammatory myokine by inhibiting TNFα and improving glucose uptake through the stimulation of AMPK signaling. This review discusses the action of IL-6 in skeletal muscle tissue dysfunction and the role of IL-6 as an “exercise factor” that modulates the immune system. This review also sheds light on the main considerations related to the treatment of muscle wasting in cancer cachexia.

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The Adipokines in Cancer Cachexia

International Journal of Molecular Sciences ◽

10.3390/ijms21144860 ◽

2020 ◽

Vol 21 (14) ◽

pp. 4860 ◽

Cited By ~ 1

Author(s):

Michele Mannelli ◽

Tania Gamberi ◽

Francesca Magherini ◽

Tania Fiaschi

Keyword(s):

Insulin Resistance ◽

Cardiovascular Disease ◽

Skeletal Muscle ◽

Metabolic Syndrome ◽

Adipose Tissue ◽

Cancer Cachexia ◽

Muscle Wasting ◽

Therapeutic Strategies ◽

Skeletal Muscle Wasting ◽

Circulating Levels

Cachexia is a devastating pathology induced by several kinds of diseases, including cancer. The hallmark of cancer cachexia is an extended weight loss mainly due to skeletal muscle wasting and fat storage depletion from adipose tissue. The latter exerts key functions for the health of the whole organism, also through the secretion of several adipokines. These hormones induce a plethora of effects in target tissues, ranging from metabolic to differentiating ones. Conversely, the decrease of the circulating level of several adipokines positively correlates with insulin resistance, metabolic syndrome, diabetes, and cardiovascular disease. A lot of findings suggest that cancer cachexia is associated with changed secretion of adipokines by adipose tissue. In agreement, cachectic patients show often altered circulating levels of adipokines. This review reported the findings of adipokines (leptin, adiponectin, resistin, apelin, and visfatin) in cancer cachexia, highlighting that to study in-depth the involvement of these hormones in this pathology could lead to the development of new therapeutic strategies.

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Structural and functional remodeling of skeletal muscle microvasculature is induced by simulated microgravity

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.2000.278.6.h1866 ◽

2000 ◽

Vol 278 (6) ◽

pp. H1866-H1873 ◽

Cited By ~ 108

Author(s):

Michael D. Delp ◽

Patrick N. Colleran ◽

M. Keith Wilkerson ◽

Matthew R. McCurdy ◽

Judy Muller-Delp

Keyword(s):

Skeletal Muscle ◽

Soleus Muscle ◽

Skeletal Muscles ◽

Gastrocnemius Muscle ◽

Fluid Pressure ◽

Hindlimb Unloading ◽

Cross Sectional ◽

Luminal Diameter ◽

Structural Remodeling

Hindlimb unloading of rats results in a diminished ability of skeletal muscle arterioles to constrict in vitro and elevate vascular resistance in vivo. The purpose of the present study was to determine whether alterations in the mechanical environment (i.e., reduced fluid pressure and blood flow) of the vasculature in hindlimb skeletal muscles from 2-wk hindlimb-unloaded (HU) rats induces a structural remodeling of arterial microvessels that may account for these observations. Transverse cross sections were used to determine media cross-sectional area (CSA), wall thickness, outer perimeter, number of media nuclei, and vessel luminal diameter of feed arteries and first-order (1A) arterioles from soleus and the superficial portion of gastrocnemius muscles. Endothelium-dependent dilation (ACh) was also determined. Media CSA of resistance arteries was diminished by hindlimb unloading as a result of decreased media thickness (gastrocnemius muscle) or reduced vessel diameter (soleus muscle). ACh-induced dilation was diminished by 2 wk of hindlimb unloading in soleus 1A arterioles, but not in gastrocnemius 1A arterioles. These results indicate that structural remodeling and functional adaptations of the arterial microvasculature occur in skeletal muscles of the HU rat; the data suggest that these alterations may be induced by reductions in transmural pressure (gastrocnemius muscle) and wall shear stress (soleus muscle).

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Exposure to cigarette smoke induces overexpression of von Hippel-Lindau tumor suppressor in mouse skeletal muscle

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00007.2012 ◽

2012 ◽

Vol 303 (6) ◽

pp. L519-L527 ◽

Cited By ~ 21

Author(s):

Vladimir T. Basic ◽

Elsa Tadele ◽

Ali Ateia Elmabsout ◽

Hongwei Yao ◽

Irfan Rahman ◽

...

Keyword(s):

Skeletal Muscle ◽

Tumor Suppressor ◽

Cigarette Smoke ◽

Muscle Fiber ◽

Exercise Tolerance ◽

Skeletal Muscles ◽

Cross Sectional Area ◽

Sectional Area ◽

Cross Sectional ◽

Von Hippel Lindau

Cigarette smoke (CS) is a well-established risk factor in the development of chronic obstructive pulmonary disease (COPD). In contrast, the extent to which CS exposure contributes to the development of the systemic manifestations of COPD, such as skeletal muscle dysfunction and wasting, remains largely unknown. Decreased skeletal muscle capillarization has been previously reported in early stages of COPD and might play an important role in the development of COPD-associated skeletal muscle abnormalities. To investigate the effects of chronic CS exposure on skeletal muscle capillarization and exercise tolerance, a mouse model of CS exposure was used. The 129/SvJ mice were exposed to CS for 6 mo, and the expression of putative elements of the hypoxia-angiogenic signaling cascade as well as muscle capillarization were studied. Additionally, functional tests assessing exercise tolerance/endurance were performed in mice. Compared with controls, skeletal muscles from CS-exposed mice exhibited significantly enhanced expression of von Hippel-Lindau tumor suppressor (VHL), ubiquitin-conjugating enzyme E2D1 (UBE2D1), and prolyl hydroxylase-2 (PHD2). In contrast, hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) expression was reduced. Furthermore, reduced muscle fiber cross-sectional area, decreased skeletal muscle capillarization, and reduced exercise tolerance were also observed in CS-exposed animals. Taken together, the current results provide evidence linking chronic CS exposure and induction of VHL expression in skeletal muscles leading toward impaired hypoxia-angiogenesis signal transduction, reduced muscle fiber cross-sectional area, and decreased exercise tolerance.

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JNK signaling contributes to skeletal muscle wasting and protein turnover in pancreatic cancer cachexia

Cancer Letters ◽

10.1016/j.canlet.2020.07.025 ◽

2020 ◽

Vol 491 ◽

pp. 70-77 ◽

Cited By ~ 2

Author(s):

Scott E. Mulder ◽

Aneesha Dasgupta ◽

Ryan J. King ◽

Jaime Abrego ◽

Kuldeep S. Attri ◽

...

Keyword(s):

Skeletal Muscle ◽

Pancreatic Cancer ◽

Protein Turnover ◽

Cancer Cachexia ◽

Muscle Wasting ◽

Jnk Signaling ◽

Skeletal Muscle Wasting

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Effects of 6 months of abiraterone acetate (AA) on muscle and adipose mass in men with metastatic castration-resistant prostate cancer (mCRPC).

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.5_suppl.222 ◽

2012 ◽

Vol 30 (5_suppl) ◽

pp. 222-222 ◽

Cited By ~ 1

Author(s):

Samuel Craig Brondfield ◽

Vivian K. Weinberg ◽

Kathryn M. Koepfgen ◽

Arturo Molina ◽

Charles J. Ryan ◽

...

Keyword(s):

Prostate Cancer ◽

Skeletal Muscle ◽

Adipose Tissue ◽

Muscle Mass ◽

Skeletal Muscle Mass ◽

Muscle Wasting ◽

Cross Sectional Area ◽

Sectional Area ◽

Cross Sectional ◽

Adipose Mass

222 Background: AA, an inhibitor of androgen biosynthesis, has been shown to prolong overall survival in patients with mCRPC who have previously been treated with chemotherapy. Androgen deprivation therapy (ADT) has been shown to result in muscle wasting in prostate cancer pts. The effects of AA on progression of muscle and fat wasting have not been characterized. We evaluated whether 6 months of AA therapy altered total skeletal muscle mass or adipose mass. Methods: 10 sequential pts who responded to AA therapy for at least 6 months and had available computed tomography (CT) scans were retrospectively selected from the phase I-II COU-AA-002 study. CT image analysis was used to quantify change from baseline in total skeletal muscle and adipose tissue after 6 months of AA treatment. Skeletal muscle and adipose tissue cross-sectional area were calculated at the L3 level using Slice-O-Matic software V4.3. Previously published regression models were used to estimate fat-free mass, fat mass and skeletal muscle mass. Paired t-tests were performed to determine the change in measurements. Results: At baseline, 7 of 10 pts were overweight or obese (body mass index [BMI] > 25 kg/m2), and none were underweight. Advanced muscle wasting (sarcopenia, previously defined as the ratio of skeletal muscle cross-sectional area at L3 level to height < 52.4 cm2/m2) was present at baseline and 6 months in 9 of 10 pts. Over 6 months of AA treatment, pts lost an average of 1.9 kg ± 1.9 kg (p = 0.13). Mean changes (kg) (±standard deviation) in total skeletal muscle mass (−0.80 ± 1.71, p = 0.18) and total non-adipose mass (−1.44 ± 3.09, p = 0.17) were not significant. A significant decrease in total adipose mass (−0.61 ± 0.84, p = 0.048) was observed. Conclusions: Sarcopenia is prevalent in pts with mCRPC. AA was not related to significantly worsening sarcopenia or overall weight loss during the first 6 months of treatment; however, this may reflect a relatively short duration of therapy and/or small sample size. A significant loss of adipose tissue was observed, which is unexpected given the known effects of ADT, which increases adipose mass. Evaluation of additional AA treated patients is ongoing.

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Stage-specific muscle wasting mechanisms in a novel cancer cachexia mouse model for ovarian granulosa cell tumor

10.1101/2020.06.16.154385 ◽

2020 ◽

Author(s):

Yaqi Zhang ◽

Jie Zhu ◽

So-Youn Kim ◽

Megan M Romero ◽

Kelly A Even ◽

...

Keyword(s):

Skeletal Muscle ◽

Weight Loss ◽

Granulosa Cell ◽

Cancer Cachexia ◽

Muscle Wasting ◽

Activin A ◽

Mice Model ◽

E3 Ligases ◽

Ovarian Granulosa Cell ◽

Specific Muscle

AbstractCachexia is a progressive muscle wasting syndrome that increases mortality risk in cancer patients, while there are still no effective treatment due to the complexity of syndrome and the lack of preclinical models. We identified a transgenic mice model with ovarian granulosa cell tumors mimic the progression of cachexia seen in humans, including drastic weight loss, skeletal muscle wasting and increased serum cachexia biomarker activin A and GDF15. Hypercatabolism was detected in skeletal muscle, having upregulation of E3 ligases Atrogin-1 and Murf-1. Our cachexia model exhibited stage-specific muscle wasting mechanisms. At precachexia stage, elevation of activin A activates p38 MAPK. Inhibition of activin A with Follistatin reversed weight loss at precachexia stage. At cachexia stage, energy stress in skeletal muscle activates AMPKα and leads to upregulation of FoxO3. Our results indicate this novel preclinical cancer cachexia model is exploitable for studying pathophysiological mechanisms and testing therapeutic agents of cachexia.

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