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Updated: Apr 15, 2026
The Colon-26 Carcinoma Tumor-bearing Mouse as a Model for the Study of Cancer Cachexia
Published on: November 30, 2016
Unacylated ghrelin counteracts mitochondrial dysfunction and neuromuscular junction disruption in cancer cachexia
Bumsoo Ahn1,2,3, Jonathan Wanagat4,5, Caroline Cleary4
1Department of Internal Medicine, Sections on Gerontology and Geriatric Medicine, Atrium Health Wake Forest Baptist, Winston-Salem, North Carolina, United States.
Abstract:
Cancer cachexia is a multifactorial metabolic syndrome that profoundly reduces muscle mass, strength, efficacy of chemotherapy, and survival, yet no effective therapy exists. Unacylated ghrelin (UnAG), the predominant form of circulating ghrelin, promotes muscle growth and mitochondrial bioenergetics, but its role in cancer cachexia remains unknown. Four- to 5-mo-old male C57Bl/6N mice were assigned to three groups: nontumor-bearing (NTB), tumor-bearing (TB), and tumor-bearing treated with UnAG (TB + UnAG). Lewis lung carcinoma cells were inoculated subcutaneously in the flank of the mice. Body weight, food intake, and tumor size were monitored for 4 wk. Lower limb muscle mass, contractile function, mitochondrial respiration, and reactive oxygen species (ROS) production were measured, in conjunction with Western blot, proteomic, and immunohistochemical analyses. Compared with NTB controls, TB mice exhibited marked loss of muscle mass and function, whereas UnAG treatment preserved ∼50% of the muscle mass and ∼70% of the contractile force. UnAG enhanced mitochondrial oxygen consumption, reduced ROS generation, and preserved mitochondrial DNA copy number and downregulated DNA mutation frequency. TB mice demonstrated increased oxidative stress and activation of protein degradation pathways, along with neuromuscular junction disruption-both of which were normalized by UnAG. These findings collectively demonstrate that UnAG mitigates cancer cachexia by modulating mitochondrial bioenergetics, oxidative and proteolytic stress, and neuromuscular junction integrity. UnAG represents a promising therapeutic candidate that may mitigate cachexia and improve both chemotherapy efficacy and the quality of life of patients with cancer.NEW & NOTEWORTHY Unacylated ghrelin prevents muscle wasting and maintains neuromuscular junction integrity and contractile function in cancer cachexia. It enhances mitochondrial respiratory capacity through elevated mitochondrial DNA copy number while limiting DNA mutation. It reduces mitochondrial reactive oxygen species (mtROS) generation, oxidative stress, and proteasome-mediated proteolysis-driven muscle degradation.
Insights
Unacylated ghrelin (UnAG) effectively combats cancer cachexia by preserving muscle mass and function. This study shows UnAG treatment mitigates metabolic decline and improves mitochondrial health in tumor-bearing mice.
Area of Science:
- Biochemistry
- Metabolic Syndrome Research
- Cancer Therapeutics
Background:
- Cancer cachexia is a debilitating syndrome characterized by muscle wasting, impacting patient survival and chemotherapy effectiveness.
- Currently, no effective therapies exist to counteract the multifaceted metabolic dysregulation seen in cancer cachexia.
- Unacylated ghrelin (UnAG), a naturally occurring ghrelin form, is known to promote muscle growth and mitochondrial function, but its role in cancer cachexia was unexplored.
Purpose of the Study:
- To investigate the therapeutic potential of unacylated ghrelin (UnAG) in mitigating cancer cachexia.
- To elucidate the mechanisms by which UnAG influences muscle mass, mitochondrial bioenergetics, and associated stress pathways in a preclinical cancer model.
Main Methods:
- A preclinical study using Lewis Lung Carcinoma-bearing mice, divided into non-tumor-bearing, tumor-bearing, and tumor-bearing treated with UnAG groups.
- Comprehensive analysis included monitoring body weight, food intake, tumor growth, muscle mass, contractile function, mitochondrial respiration, oxidative stress markers (ROS), and proteomic/immunohistochemical assessments.
- Evaluated UnAG's impact on mitochondrial DNA integrity, protein degradation pathways, and neuromuscular junction stability.
Main Results:
- UnAG treatment preserved approximately 50% of muscle mass and 70% of contractile force in tumor-bearing mice compared to untreated controls.
- UnAG significantly enhanced mitochondrial oxygen consumption, reduced reactive oxygen species (ROS) production, and maintained mitochondrial DNA integrity.
- UnAG normalized increased oxidative stress, attenuated protein degradation pathways, and restored neuromuscular junction integrity disrupted by tumor progression.
Conclusions:
- Unacylated ghrelin (UnAG) demonstrates significant efficacy in mitigating cancer cachexia by targeting key pathological pathways.
- UnAG acts by improving mitochondrial bioenergetics, reducing oxidative and proteolytic stress, and preserving neuromuscular junction integrity.
- UnAG shows promise as a therapeutic agent to improve cachexia symptoms, enhance chemotherapy outcomes, and improve the quality of life for cancer patients.
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