Weight Loss in Cancer Patients Correlates With p38β MAPK Activation in Skeletal Muscle

Unintentional weight loss, a first clinical sign of muscle wasting, is a major threat to cancer survival without a defined etiology. We previously identified in mice that p38β MAPK mediates cancer-induced muscle wasting by stimulating protein catabolism. However, whether this mechanism is relevant to humans is unknown. In this study, we recruited men with cancer and weight loss (CWL) or weight stable (CWS), and non-cancer controls (NCC), who were consented to rectus abdominis (RA) biopsy and blood sampling (n = 20/group). In the RA of both CWS and CWL, levels of activated p38β MAPK and its effectors in the catabolic pathways were higher than in NCC, with progressively higher active p38β MAPK detected in CWL. Remarkably, levels of active p38β MAPK correlated with weight loss. Plasma analysis for factors that activate p38β MAPK revealed higher levels in some cytokines as well as Hsp70 and Hsp90 in CWS and/or CWL. Thus, p38β MAPK appears a biomarker of weight loss in cancer patients.

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Continued Weight Loss and Sarcopenia Predict Poor Outcomes in Locally Advanced Pancreatic Cancer Treated with Chemoradiation

Cancers ◽

10.3390/cancers11050709 ◽

2019 ◽

Vol 11 (5) ◽

pp. 709 ◽

Cited By ~ 10

Author(s):

Patrick Naumann ◽

Jonathan Eberlein ◽

Benjamin Farnia ◽

Thilo Hackert ◽

Jürgen Debus ◽

...

Keyword(s):

Skeletal Muscle ◽

Pancreatic Cancer ◽

Weight Loss ◽

Muscle Mass ◽

Muscle Wasting ◽

Statistical Tests ◽

Locally Advanced ◽

Advanced Pancreatic Cancer ◽

Skeletal Muscle Index ◽

Poor Outcomes

Background: Surgical resection offers the best chance of survival in patients with pancreatic cancer, but those with locally advanced disease (LAPC) are usually not surgical candidates. This cohort often receives either neoadjuvant chemotherapy or chemoradiation (CRT), but unintended weight loss coupled with muscle wasting (sarcopenia) can often be observed. Here, we report on the predictive value of changes in weight and muscle mass in 147 consecutive patients with LAPC treated with neoadjuvant CRT. Methods: Clinicopathologic data were obtained via a retrospective chart review. The abdominal skeletal muscle area (SMA) at the third lumbar vertebral body was determined via computer tomographic (CT) scans as a surrogate for the muscle mass and skeletal muscle index (SMI) calculated. Uni- and multi-variable statistical tests were performed to assess for impact on survival. Results: Weight loss (14.5 vs. 20.3 months; p = 0.04) and loss of muscle mass (15.1 vs. 22.2 months; p = 0.007) were associated with poor outcomes. The highest survival was observed in patients who had neither cachectic weight loss nor sarcopenia (27 months), with improved survival seen in those who ultimately received a resection (23 vs. 10 months; p < 0.001). Cox regression revealed that either continued weight loss or continued muscle wasting (SMA reduction) was predictive of poor outcomes, whereas a sarcopenic SMI was not. Conclusions: Loss of weight and lean muscle in patients with LAPC is prognostic when persistent. Therefore, both should be assessed longitudinally and considered before surgery.

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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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Prevalence and impact of hypogonadism in cancer patients with severe muscle wasting in phase IIb enobosarm trial.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e19582 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e19582-e19582

Author(s):

Mitchell S. Steiner ◽

Adrian Dobs ◽

Mary Ann Johnston ◽

Michael L. Hancock ◽

Ronald A. Morton ◽

...

Keyword(s):

Weight Loss ◽

Physical Function ◽

Cancer Patients ◽

Muscle Wasting ◽

Controlled Trial ◽

Performance Status ◽

Lymphocytic Leukemia ◽

Double Blind ◽

Poor Outcomes ◽

Multi Center Study

e19582 Background: Hypogonadism has been associated with weight loss and poor outcomes in cancer patients. Up to 50% of males with advanced cancer are hypogonadal at presentation or during the course of treatment. Wasting in cancer patients has also been associated with a decline in physical function and performance status and has major public health significance. We conducted a Phase IIb randomized, double blind, placebo controlled, multi-center study to evaluate the effect of enobosarm on muscle wasting and physical function in cancer patients. Methods: Patients (n=159) were randomized to oral enobosarm (1 or 3 mg) or placebo daily for 16 wks. Patients were males >45 y and postmenopausal females, had ≥2% weight loss in the 6 mths prior to randomization, BMI <35 and either NSCLC, colorectal cancer, non-Hodgkins lymphoma, chronic lymphocytic leukemia or breast cancer. We report on the incidence and impact of hypogonadism (T<300 ng/dL) in this population. Results: Baseline testosterone levels were available for 93 of 103 men. 60% of male patients were hypogonadal at randomization. Distribution of hypogonadism was similar across cancers; however hypogonadal men were less likely to complete the study. Baseline T levels were positively correlated with weight loss (r=0.32, p=0.002,) with hypogonadal men demonstrating greater weight loss in the previous six months (median, -9.5%). Baseline physical function as measured by stair climb power was higher among eugonadal males compared to hypogonadal males (84.5 watts vs 70.6 watts; p=0.016). Enobosarm significantly improved physical function in this population regardless of baseline gonadal status (hypogonadal: 18.7%, p=0.0061; eugonadal: 13.2%, p=0.0032). The magnitude of improvement was greater in hypogonadal men. Conclusions: Hypogonadism is common in male cancer patients and is correlated with weight loss and diminished physical function. In this randomized, placebo controlled trial, enobosarm improved physical function in both hypogonadal and eugonadal men despite poorer baseline physical function in hypogonadal patients. These data provide evidence that enobosarm may play an important role in the management of cancer related muscle wasting.

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Weight loss and muscle wasting in pediatric cancer patients undergoing radiotherapy

Clinical Nutrition ESPEN ◽

10.1016/j.clnesp.2021.09.459 ◽

2021 ◽

Vol 46 ◽

pp. S706

Author(s):

K.J.T. Guedes ◽

R.L. Ferretti ◽

T.L. Almeida ◽

C.F. Marçon ◽

M.Y.R.S. Moretti ◽

...

Keyword(s):

Weight Loss ◽

Cancer Patients ◽

Pediatric Cancer ◽

Muscle Wasting ◽

Pediatric Cancer Patients

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Quantitative Analysis of Skeletal Muscle Wasting During Chemoradiotherapy Predicts Toxicity and Survival Outcomes in Gastric Cancer Patients

International Journal of Radiation Oncology*Biology*Physics ◽

10.1016/j.ijrobp.2019.06.2051 ◽

2019 ◽

Vol 105 (1) ◽

pp. E211

Author(s):

W. Yang ◽

J. Wang ◽

F. Xia ◽

M. Zhou ◽

G. Li ◽

...

Keyword(s):

Gastric Cancer ◽

Skeletal Muscle ◽

Quantitative Analysis ◽

Cancer Patients ◽

Muscle Wasting ◽

Survival Outcomes ◽

Skeletal Muscle Wasting ◽

Gastric Cancer Patients

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Growth Hormone and Insulin Reverse Net Whole Body and Skeletal Muscle Protein Catabolism in Cancer Patients

Annals of Surgery ◽

10.1097/00000658-199209000-00007 ◽

1992 ◽

Vol 216 (3) ◽

pp. 280-290 ◽

Cited By ~ 54

Author(s):

RONALD F. WOLF ◽

DAVID B. PEARLSTONE ◽

ELLIOT NEWMAN ◽

MARTIN J. HESLIN ◽

AMNON GONENNE ◽

...

Keyword(s):

Skeletal Muscle ◽

Growth Hormone ◽

Cancer Patients ◽

Muscle Protein ◽

Whole Body ◽

Protein Catabolism ◽

Skeletal Muscle Protein

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Bioactivity of skeletal muscle proteolysis-inducing factors in the plasma proteins from cancer patients with weight loss

British Journal of Cancer ◽

10.1038/bjc.1991.159 ◽

1991 ◽

Vol 63 (5) ◽

pp. 705-710 ◽

Cited By ~ 31

Author(s):

JE Belizario ◽

M Katz ◽

E Chenker ◽

I Raw

Keyword(s):

Skeletal Muscle ◽

Weight Loss ◽

Cancer Patients ◽

Plasma Proteins ◽

Inducing Factors

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CALPAIN activity is increased in skeletal muscle from gastric cancer patients with no or minimal weight loss

Muscle & Nerve ◽

10.1002/mus.21893 ◽

2011 ◽

Vol 43 (3) ◽

pp. 410-414 ◽

Cited By ~ 30

Author(s):

Ira J. Smith ◽

Zaira Aversa ◽

Per-Olof Hasselgren ◽

Fabio Pacelli ◽

Fausto Rosa ◽

...

Keyword(s):

Gastric Cancer ◽

Skeletal Muscle ◽

Weight Loss ◽

Cancer Patients ◽

Calpain Activity ◽

Minimal Weight ◽

Gastric Cancer Patients

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Sex Differences in Cancer Cachexia

Current Osteoporosis Reports ◽

10.1007/s11914-020-00628-w ◽

2020 ◽

Vol 18 (6) ◽

pp. 646-654

Author(s):

Xiaoling Zhong ◽

Teresa A. Zimmers

Keyword(s):

Weight Loss ◽

Sex Differences ◽

Cancer Patients ◽

Cancer Cachexia ◽

Muscle Wasting ◽

Fiber Type ◽

Global Gene Expression ◽

Skeletal Muscle Wasting ◽

Progressive Weight Loss ◽

And Function

Abstract Purpose of Review Cachexia, a feature of cancer and other chronic diseases, is marked by progressive weight loss and skeletal muscle wasting. This review aims to highlight the sex differences in manifestations of cancer cachexia in patients, rodent models, and our current understanding of the potential mechanisms accounting for these differences. Recent Findings Male cancer patients generally have higher prevalence of cachexia, greater weight loss or muscle wasting, and worse outcomes compared with female cancer patients. Knowledge is increasing about sex differences in muscle fiber type and function, mitochondrial metabolism, global gene expression and signaling pathways, and regulatory mechanisms at the levels of sex chromosomes vs. sex hormones; however, it is largely undetermined how such sex differences directly affect the susceptibility to stressors leading to muscle wasting in cancer cachexia. Summary Few studies have investigated basic mechanisms underlying sex differences in cancer cachexia. A better understanding of sex differences would improve cachexia treatment in both sexes.

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