Protein imbalance in the development of skeletal muscle wasting in tumour‐bearing mice

Abstract

BackgroundCancer cachexia occurs in approximately 80% of cancer patients and is a key contributor to cancer‐related death. The mechanisms controlling development of tumour‐induced muscle wasting are not fully elucidated. Specifically, the progression and development of cancer cachexia are underexplored. Therefore, we examined skeletal muscle protein turnover throughout the development of cancer cachexia in tumour‐bearing mice.MethodsLewis lung carcinoma (LLC) was injected into the hind flank of C57BL6/J mice at 8 weeks age with tumour allowed to develop for 1, 2, 3, or 4 weeks and compared with PBS injected control. Muscle size was measured by cross‐sectional area analysis of haematoxylin and eosin stained tibialis anterior muscle. 2H2O was used to assess protein synthesis throughout the development of cancer cachexia. Immunoblot and RT‐qPCR were used to measure regulators of protein turnover. TUNEL staining was utilized to measure apoptotic nuclei. LLC conditioned media (LCM) treatment of C2C12 myotubes was used to analyse cancer cachexia in vitro.ResultsMuscle cross‐sectional area decreased ~40% 4 weeks following tumour implantation. Myogenic signalling was suppressed in tumour‐bearing mice as soon as 1 week following tumour implantation, including lower mRNA contents of Pax7, MyoD, CyclinD1, and Myogenin, when compared with control animals. AchRδ and AchRε mRNA contents were down‐regulated by ~50% 3 weeks following tumour implantation. Mixed fractional synthesis rate protein synthesis was ~40% lower in 4 week tumour‐bearing mice when compared with PBS controls. Protein ubiquitination was elevated by ~50% 4 weeks after tumour implantation. Moreover, there was an increase in autophagy machinery after 4 weeks of tumour growth. Finally, ERK and p38 MAPK phosphorylations were fourfold and threefold greater than control muscle 4 weeks following tumour implantation, respectively. Inhibition of p38 MAPK, but not ERK MAPK, in vitro partially rescued LCM‐induced loss of myotube diameter.ConclusionsOur findings work towards understanding the pathophysiological signalling in skeletal muscle in the initial development of cancer cachexia. Shortly following the onset of the tumour‐bearing state alterations in myogenic regulatory factors are apparent, suggesting early onset alterations in the capacity for myogenic induction. Cancer cachexia presents with a combination of a loss of protein synthesis and increased markers of protein breakdown, specifically in the ubiquitin‐proteasome system. Also, p38 MAPK may be a potential therapeutic target to combat cancer cachexia via a p38‐FOX01‐atrogene‐ubiquitin‐proteasome mechanism.

Muscle loss during primary debulking surgery and chemotherapy predicts poor survival in advanced‐stage ovarian cancer

“…During the course of cancer therapy, body composition may change and influence outcomes of cancer patients . Body composition changes could be associated with systemic inflammation, treatment‐related toxicity, physical inactivity, malnutrition, cancer invasiveness, and cancer therapy . Therefore, evaluating the body composition at a single specific time point may not help in predicting survival.…”

Muscle radiodensity loss during cancer therapy is predictive for poor survival in advanced endometrial cancer

“…Changes in body composition during cancer therapy have been associated with treatment‐related toxicity, physical inactivity, malnutrition, cancer invasiveness, and cancer therapy, which in turn could influence patient outcomes . Therefore, the prognostic value of body composition measurements in stage III EC needs to be evaluated.…”

“…16,17 Changes in body composition during cancer therapy have been associated with treatment-related toxicity, physical inactivity, malnutrition, cancer invasiveness, and cancer therapy, which in turn could influence patient outcomes. [18][19][20][21][22][23][24][25][26] Therefore, the prognostic value of body composition measurements in stage III EC needs to be evaluated. It has been shown that the cross-sectional areas of skeletal muscle and adipose tissue on a single computed tomography (CT) slice at the level of the third lumbar vertebra are strongly correlated with the total body skeletal muscle and adipose tissues.…”

Muscle Loss after Chemoradiotherapy as a Biomarker of Distant Failures in Locally Advanced Cervical Cancer

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