Continued use of alcohol accelerates cancer cachexia and impairs ability to induce 4E-BP1 but not p70S6K phosphorylation following muscle contraction
Authors: Steiner Jennifer , Boykin Jake , Tice Abigail , Laudato Joseph , Murphy Robert 
Published: May 2024

A primary co-morbidity of cancer is cancer cachexia characterized by the wasting of adipose tissue and skeletal muscle. Up to 80% of cancer patients may suffer from this wasting condition leading to reduced quality of life, poor treatment effectiveness and increased morbidity and mortality. The risk of cancer cachexia is enhanced in those with poor lifestyle habits including the habitual consumption of alcohol both prior to a cancer diagnosis and when consumption is continued during disease progression. The use of muscle contraction to improve outcomes in cachexia has been explored in alcohol naïve models with some success, however alcohol at high doses induces anabolic resistance preventing protein synthesis in response to an anabolic stimuli like muscle contraction. Therefore, muscle contraction may not be a suffcient stimuli to overcome cachexia induced catabolism when alcohol has been or is currently being consumed. The purpose of this work was to determine if alcohol induces anabolic resistance in tumor bearing mice or whether it can be used as a therapeutic intervention. It was hypothesized that alcohol would inhibit the stimulation of markers of the anabolic mTORC1 pathway in tumor bearing mice. METHODS: Female BALB/c mice, 12 weeks of age, were randomized into 4 groups (n = 12-14/group): control diet (CON), control diet-cancer (Cancer), Prior EtOH diet-cancer (PE-Cancer), and EtOH diet-cancer (E-cancer). All mice received the isocaloric Lieber DeCarli liquid diet with EtOH mice consuming 20% kcal/daily EtOH for 6 weeks. After 6 weeks, PE-cancer switched to the non-alcohol diet and all cancer groups had C26 carcinoma cells implanted. A single bout of maximal stimulated muscle contraction (10sets of 6 repetitions at 100Hz) was performed ~2 weeks later and muscles were collected 4 hours post contraction. RESULTS: E-cancer lost ~10% body mass, while no other cancer groups exhibited a significant loss in body mass indicating early-stage cachexia. Spleen mass was elevated in all cancer groups relative to control, while quadricep and gastrocnemius muscle weights were reduced in PE-cancer and E-cancer compared to CON. Muscle contraction significantly increased the phosphorylation of S6K1 Thr389 in all of groups except for PE-cancer where a strong trend was still detected (p=0.06). In contrast, phosphorylation of 4EBP1 Ser65 was only increased by muscle contraction in CON, as cancer prevented its stimulation. Therefore, despite accelerating body weight loss, continued alcohol consumption or prior alcohol consumption did not completely impair the anabolic response to maximally stimulated muscle contraction during the early stages of cancer cachexia. However, measurement of rates of degradation and synthesis over time are required to make further conclusions as to its therapeutic potential.

Florida Department of Health Grant # 9BC03.

This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.