Increased hypoxia-inducible factor-1α in striated muscle of tumor-bearing mice

Cancer cachexia is a progressive wasting disease resulting in significant effects on the quality of life and high mortality. Most studies on cancer cachexia have focused on skeletal muscle; however, the heart is now recognized as a major site of cachexia-related effects. To elucidate possible mechanisms, a proteomic study was performed on the left ventricles of colon-26 (C26) adenocarcinoma tumor-bearing mice. The results revealed several changes in proteins involved in metabolism. An integrated pathway analysis of the results revealed a common mediator in hypoxia-inducible factor-1α (HIF-1α). Work by other laboratories has shown that extensive metabolic restructuring in the C26 mouse model causes changes in gene expression that may be affected directly by HIF-1α, such as glucose metabolic genes. M-mode echocardiography showed progressive decline in heart function by day 19, exhibited by significantly decreased ejection fraction and fractional shortening, along with posterior wall thickness. Using Western blot analysis, we confirmed that HIF-1α is significantly upregulated in the heart, whereas there were no changes in its regulatory proteins, prolyl hydroxylase domain-containing protein 2 (PHD2) and von Hippel-Lindau protein (VHL). PHD2 requires both oxygen and iron as cofactors for the hydroxylation of HIF-1α, marking it for ubiquination via VHL and subsequent destruction by the proteasome complex. We examined venous blood gas values in the tumor-bearing mice and found significantly lower oxygen concentration compared with control animals in the third week after tumor inoculation. We also examined select skeletal muscles to determine whether they are similarly affected. In the diaphragm, extensor digitorum longus, and soleus, we found significantly increased HIF-1α in tumor-bearing mice, indicating a hypoxic response, not only in the heart, but also in skeletal muscle. These results indicate that HIF-1α may contribute, in part, to the metabolic changes that occur during cancer cachexia. NEW & NOTEWORTHY We used proteomics and metadata analysis software to identify contributors to metabolic changes in striated muscle during cancer cachexia. We found increased expression of hypoxia-inducible factor-1α in the heart and skeletal muscle, suggesting a potential target for the therapeutic treatment of cancer cachexia.

Download Full-text

Faculty Opinions recommendation of Myeloid hypoxia-inducible factor-1α is essential for skeletal muscle regeneration in mice.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718016862.793490651 ◽

2014 ◽

Author(s):

James Tidball

Keyword(s):

Skeletal Muscle ◽

Muscle Regeneration ◽

Hypoxia Inducible Factor ◽

Skeletal Muscle Regeneration ◽

Hypoxia Inducible Factor 1Α

Download Full-text

Myeloid Hypoxia-Inducible Factor-1α Is Essential for Skeletal Muscle Regeneration in Mice

The Journal of Immunology ◽

10.4049/jimmunol.1103779 ◽

2013 ◽

Vol 191 (1) ◽

pp. 407-414 ◽

Cited By ~ 27

Author(s):

Nina Scheerer ◽

Nathalie Dehne ◽

Christian Stockmann ◽

Sandra Swoboda ◽

Hideo A. Baba ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Regeneration ◽

Hypoxia Inducible Factor ◽

Skeletal Muscle Regeneration ◽

Hypoxia Inducible Factor 1Α

Download Full-text

Higher skeletal muscle protein synthesis and lower breakdown after chemotherapy in cachectic mice

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.2001.281.1.r133 ◽

2001 ◽

Vol 281 (1) ◽

pp. R133-R139 ◽

Cited By ~ 20

Author(s):

S. E. Samuels ◽

A. L. Knowles ◽

T. Tilignac ◽

E. Debiton ◽

J. C. Madelmont ◽

...

Keyword(s):

Skeletal Muscle ◽

Protein Synthesis ◽

Muscle Mass ◽

Skeletal Muscle Mass ◽

Cancer Cachexia ◽

Muscle Protein ◽

Muscle Protein Synthesis ◽

Human Condition ◽

Skeletal Muscle Protein ◽

Tumor Bearing

The influence of cancer cachexia and chemotherapy and subsequent recovery of skeletal muscle protein mass and turnover was investigated in mice. Cancer cachexia was induced using colon 26 adenocarcinoma, which is characteristic of the human condition, and can be cured with 100% efficacy using an experimental nitrosourea, cystemustine (C6H12CIN3O4S). Reduced food intake was not a factor in these studies. Three days after cachexia began, healthy and tumor-bearing mice were given a single intraperitoneal injection of cystemustine (20 mg/kg). Skeletal muscle mass in tumor-bearing mice was 41% lower ( P < 0.05) than in healthy mice 2 wk after cachexia began. Skeletal muscle wasting was mediated initially by decreased protein synthesis (−38%; P < 0.05) and increased degradation (+131%; P < 0.05); later wasting resulted solely from decreased synthesis (∼−54 to −69%; P < 0.05). Acute cytotoxicity of chemotherapy did not appear to have an important effect on skeletal muscle protein metabolism in either healthy or tumor-bearing mice. Recovery began 2 days after treatment; skeletal muscle mass was only 11% lower than in healthy mice 11 days after chemotherapy. Recovery of skeletal muscle mass was affected initially by decreased protein degradation (−80%; P < 0.05) and later by increased protein synthesis (+46 to +73%; P < 0.05) in cured compared with healthy mice. This study showed that skeletal muscle wasted from cancer cachexia and after chemotherapeutic treatment is able to generate a strong anabolic response by making powerful changes to protein synthesis and degradation.

Download Full-text

Hmox1 (Heme Oxygenase-1) Protects Against Ischemia-Mediated Injury via Stabilization of HIF-1α (Hypoxia-Inducible Factor-1α)

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.120.315393 ◽

2020 ◽

Author(s):

Louise L. Dunn ◽

Stephanie M.Y. Kong ◽

Sergey Tumanov ◽

Weiyu Chen ◽

James Cantley ◽

...

Keyword(s):

Skeletal Muscle ◽

Carbon Monoxide ◽

Blood Flow ◽

Heme Oxygenase ◽

Hypoxia Inducible Factor ◽

Ischemic Injury ◽

Heme Oxygenase 1 ◽

Wild Type ◽

Tissue Necrosis ◽

Hypoxia Inducible Factor 1Α

Objective: Hmox1 (heme oxygenase-1) is a stress-induced enzyme that catalyzes the degradation of heme to carbon monoxide, iron, and biliverdin. Induction of Hmox1 and its products protect against cardiovascular disease, including ischemic injury. Hmox1 is also a downstream target of the transcription factor HIF-1α (hypoxia-inducible factor-1α), a key regulator of the body’s response to hypoxia. However, the mechanisms by which Hmox1 confers protection against ischemia-mediated injury remain to be fully understood. Approach and Results: Hmox1 deficient ( Hmox1 –/– ) mice had impaired blood flow recovery with severe tissue necrosis and autoamputation following unilateral hindlimb ischemia. Autoamputation preceded the return of blood flow, and bone marrow transfer from littermate wild-type mice failed to prevent tissue injury and autoamputation. In wild-type mice, ischemia-induced expression of Hmox1 in skeletal muscle occurred before stabilization of HIF-1α. Moreover, HIF-1α stabilization and glucose utilization were impaired in Hmox1 –/– mice compared with wild-type mice. Experiments exposing dermal fibroblasts to hypoxia (1% O 2 ) recapitulated these key findings. Metabolomics analyses indicated a failure of Hmox1 –/– mice to adapt cellular energy reprogramming in response to ischemia. Prolyl-4-hydroxylase inhibition stabilized HIF-1α in Hmox1 –/– fibroblasts and ischemic skeletal muscle, decreased tissue necrosis and autoamputation, and restored cellular metabolism to that of wild-type mice. Mechanistic studies showed that carbon monoxide stabilized HIF-1α in Hmox1 –/– fibroblasts in response to hypoxia. Conclusions: Our findings suggest that Hmox1 acts both downstream and upstream of HIF-1α, and that stabilization of HIF-1α contributes to Hmox1’s protection against ischemic injury independent of neovascularization.

Download Full-text

A single bout of exercise with high mechanical loading induces the expression of Cyr61/CCN1 and CTGF/CCN2 in human skeletal muscle

Journal of Applied Physiology ◽

10.1152/japplphysiol.00531.2007 ◽

2007 ◽

Vol 103 (4) ◽

pp. 1395-1401 ◽

Cited By ~ 32

Author(s):

Riikka Kivelä ◽

Heikki Kyröläinen ◽

Harri Selänne ◽

Paavo V. Komi ◽

Heikki Kainulainen ◽

...

Keyword(s):

Skeletal Muscle ◽

Mrna Expression ◽

Mechanical Loading ◽

Human Skeletal Muscle ◽

Hypoxia Inducible Factor ◽

Tissue Growth ◽

Vastus Lateralis Muscle ◽

Ccn Proteins ◽

Mrna Levels ◽

Hypoxia Inducible Factor 1Α

High mechanical loading was hypothesized to induce the expression of angiogenic and/or lymphangiogenic extracellular matrix (ECM) proteins in skeletal muscle. Eight men performed a strenuous exercise protocol, which consisted of 100 unilateral maximal drop jumps followed by submaximal jumping until exhaustion. Muscle biopsies were taken 30 min and 48 h postexercise from the vastus lateralis muscle and analyzed for the following parameters: mRNA and protein expression of ECM-associated CCN proteins [cysteine-rich angiogenic protein 61 (Cyr61)/CCN1, connective tissue growth factor (CTGF)/CCN2], and mRNA expression of vascular endothelial growth factors (VEGFs) and hypoxia-inducible factor-1α. The mRNA expression of Cyr61 and CTGF increased 30 min after the exercise (14- and 2.5-fold, respectively; P < 0.001). Cyr61 remained elevated 48 h postexercise (threefold; P < 0.05). The mRNA levels of VEGF-A, VEGF-B, VEGF-C, VEGF-D, or hypoxia-inducible factor-1α did not change significantly at either 30 min or 48 h postexercise; however, the variation between subjects increased markedly in VEGF-A and VEGF-B mRNA. Cyr61 protein levels were higher at both 30 min and 48 h after the exercise compared with the control ( P < 0.05). Cyr61 and CTGF proteins were localized to muscle fibers and the surrounding ECM by immunohistochemistry. Fast fibers stained more intensively than slow fibers. In conclusion, mechanical loading induces rapid expression of CCN proteins in human skeletal muscle. This may be one of the early mechanisms involved in skeletal muscle remodeling after exercise, since Cyr61 and CTGF regulate the expression of genes involved in angiogenesis and ECM remodeling.

Download Full-text

Emodin and rhein decrease levels of hypoxia-inducible factor-1α in human pancreatic cancer cells and attenuate cancer cachexia in athymic mice carrying these cells

Oncotarget ◽

10.18632/oncotarget.21330 ◽

2017 ◽

Vol 8 (50) ◽

pp. 88008-88020 ◽

Cited By ~ 15

Author(s):

Lijuan Hu ◽

Rui Cui ◽

Hongyi Liu ◽

Feng Wang

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Cancer Cachexia ◽

Hypoxia Inducible Factor ◽

Human Pancreatic Cancer ◽

Athymic Mice ◽

Hypoxia Inducible Factor 1Α ◽

Pancreatic Cancer Cells

Download Full-text

Neurohypophyseal hormones and skeletal muscle: a tale of two faces

European Journal of Translational Myology ◽

10.4081/ejtm.2019.8899 ◽

2020 ◽

Vol 30 (1) ◽

pp. 53-57

Author(s):

Alexandra Benoni ◽

Alessandra Renzini ◽

Giorgia Cavioli ◽

Sergio Adamo

Keyword(s):

Skeletal Muscle ◽

Muscle Atrophy ◽

Cancer Cachexia ◽

Muscle Wasting ◽

Striated Muscle ◽

Cardiac Atrophy ◽

Neurohypophyseal Hormones

The neurohypophyseal hormones vasopressin and oxytocin were invested, in recent years, with novel functions upon striated muscle, regulating its differentiation, trophism, and homeostasis. Recent studies highlight that these hormones not only target skeletal muscle but represent novel myokines. We discuss the possibility of exploiting the muscle hypertrophying activity of oxytocin to revert muscle atrophy, including cancer cachexia muscle wasting. Furthermore, the role of oxytocin in cardiac homeostasis and the possible role of cardiac atrophy as a concause of death in cachectic patients is discussed.

Download Full-text

Antibody-directed myostatin inhibition enhances muscle mass and function in tumor-bearing mice

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00121.2011 ◽

2011 ◽

Vol 301 (3) ◽

pp. R716-R726 ◽

Cited By ~ 58

Author(s):

Kate T. Murphy ◽

Annabel Chee ◽

Ben G. Gleeson ◽

Timur Naim ◽

Kristy Swiderski ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Mass ◽

Muscle Atrophy ◽

Cancer Cachexia ◽

Diaphragm Muscle ◽

Oxidative Enzymes ◽

Saline Control ◽

Tumor Bearing ◽

Myostatin Inhibition ◽

And Function

Cancer cachexia describes the progressive skeletal muscle wasting and weakness in many cancer patients and accounts for >20% of cancer-related deaths. We tested the hypothesis that antibody-directed myostatin inhibition would attenuate the atrophy and loss of function in muscles of tumor-bearing mice. Twelve-week-old C57BL/6 mice received a subcutaneous injection of saline (control) or Lewis lung carcinoma (LLC) tumor cells. One week later, mice received either once weekly injections of saline (control, n = 12; LLC, n = 9) or a mouse chimera of anti-human myostatin antibody (PF-354, 10 mg·kg−1·wk−1, LLC+PF-354, n = 11) for 5 wk. Injection of LLC cells reduced muscle mass and maximum force of tibialis anterior (TA) muscles by 8–10% ( P < 0.05), but the muscle atrophy and weakness were prevented with PF-354 treatment ( P > 0.05). Maximum specific (normalized) force of diaphragm muscle strips was reduced with LLC injection ( P < 0.05) but was not improved with PF-354 treatment ( P > 0.05). PF-354 enhanced activity of oxidative enzymes in TA and diaphragm muscles of tumor-bearing mice by 118% and 89%, respectively ( P < 0.05). Compared with controls, apoptosis that was not of myofibrillar or satellite cell origin was 140% higher in TA muscle cross sections from saline-treated LLC tumor-bearing mice ( P < 0.05) but was not different in PF-354-treated tumor-bearing mice ( P > 0.05). Antibody-directed myostatin inhibition attenuated the skeletal muscle atrophy and loss of muscle force-producing capacity in a murine model of cancer cachexia, in part by reducing apoptosis. The improvements in limb muscle mass and function highlight the therapeutic potential of antibody-directed myostatin inhibition for cancer cachexia.

Download Full-text

Comparative Transcriptomic Profiling of Organs Associated With Metabolic Dysfunction in Cancer-Induced Cachexia

Current Developments in Nutrition ◽

10.1093/cdn/nzab041_016 ◽

2021 ◽

Vol 5 (Supplement_2) ◽

pp. 501-501

Author(s):

Ji-Won Heo ◽

Sung-Eun Kim

Keyword(s):

Gene Expression ◽

Skeletal Muscle ◽

Adipose Tissue ◽

Energy Metabolism ◽

Cancer Cachexia ◽

Gene Set Enrichment Analysis ◽

Glutamine Metabolism ◽

Metabolic Dysfunction ◽

Network Analyses ◽

Tumor Bearing

Abstract Objectives Approximately 50–80% of cancer patients suffer from cachexia represented by weight loss mainly due to loss of skeletal muscle. Cancer-induced cachexia is a complex metabolic syndrome associated with not only systemic inflammation but also perturbations to energy metabolism. In this study, we profiled gene expression patterns of different organs in CT-26 tumor bearing mice in order to understand metabolic dysfunction in cancer cachexia. Methods The transcriptomic profiles of skeletal muscle, adipose tissue, and liver of CT26-tumor bearing mice were generated using SurePrint G3 Mouse Gene Expression 8 × 60 K v2 (Agilent, Inc.). Functional and network analyses were performed using Gene Set Enrichment Analysis and Ingenuity Pathway Analysis (QIAGEN). Results We identified 299, 508, and 1,311 genes differentially regulated in skeletal muscle, adipose tissue, and liver, respectively. In the skeletal muscle, lipid biosynthetic process and mitochondrial electron transport were negatively regulated and network involved in glutamine metabolism was up-regulated. In adipose tissue, tricarboxylic acid cycle was down-regulated and lipid metabolism was associated with several genes including Thrsp, Plvap, and Sphk1. In the liver, regulation of gluconeogenesis was down-regulated, while production of lactic acid and uptake of D-glucose were related with H6pd and Pkm whose expression was up-regulated during cancer cachexia. Furthermore, the top network matched by genes commonly up-regulated in all organs included Bcl3, Csf2rb, Fcgr2a, and Lilrb3, which are known to be associated with inflammation and muscle wasting. Conclusions Our data suggest that skeletal muscle, adipose tissue, and liver present distinct gene expression profiles associated with inflammation and energy metabolism and several genes up-regulated in all organs might be candidate biomarkers for the prevention and early detection of cancer cachexia. Funding Sources This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education.

Download Full-text