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Review
. 2023 Jun;14(3):1150-1167.
doi: 10.1002/jcsm.13073. Epub 2023 Mar 2.

Molecular mechanisms of cancer cachexia-related loss of skeletal muscle mass: data analysis from preclinical and clinical studies

Agnès Martin  1   2 , Yann S Gallot  3   2 , Damien Freyssenet  1
Affiliations
Review

Molecular mechanisms of cancer cachexia-related loss of skeletal muscle mass: data analysis from preclinical and clinical studies

Agnès Martin et al. J Cachexia Sarcopenia Muscle. 2023 Jun.

Abstract

Cancer cachexia is a systemic hypoanabolic and catabolic syndrome that diminishes the quality of life of cancer patients, decreases the efficiency of therapeutic strategies and ultimately contributes to decrease their lifespan. The depletion of skeletal muscle compartment, which represents the primary site of protein loss during cancer cachexia, is of very poor prognostic in cancer patients. In this review, we provide an extensive and comparative analysis of the molecular mechanisms involved in the regulation of skeletal muscle mass in human cachectic cancer patients and in animal models of cancer cachexia. We summarize data from preclinical and clinical studies investigating how the protein turnover is regulated in cachectic skeletal muscle and question to what extent the transcriptional and translational capacities, as well as the proteolytic capacity (ubiquitin-proteasome system, autophagy-lysosome system and calpains) of skeletal muscle are involved in the cachectic syndrome in human and animals. We also wonder how regulatory mechanisms such as insulin/IGF1-AKT-mTOR pathway, endoplasmic reticulum stress and unfolded protein response, oxidative stress, inflammation (cytokines and downstream IL1ß/TNFα-NF-κB and IL6-JAK-STAT3 pathways), TGF-ß signalling pathways (myostatin/activin A-SMAD2/3 and BMP-SMAD1/5/8 pathways), as well as glucocorticoid signalling, modulate skeletal muscle proteostasis in cachectic cancer patients and animals. Finally, a brief description of the effects of various therapeutic strategies in preclinical models is also provided. Differences in the molecular and biochemical responses of skeletal muscle to cancer cachexia between human and animals (protein turnover rates, regulation of ubiquitin-proteasome system and myostatin/activin A-SMAD2/3 signalling pathways) are highlighted and discussed. Identifying the various and intertwined mechanisms that are deregulated during cancer cachexia and understanding why they are decontrolled will provide therapeutic targets for the treatment of skeletal muscle wasting in cancer patients.

Keywords: Autophagy-lysosome; Cancer cachexia; Glucocorticoids; Inflammation; Myostatin; Oxidative stress; Proteostasis; Skeletal muscle; Ubiquitin-proteasome.

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Conflict of interest statement

A.M., Y.S.G. and D.F. declare that they have no conflict of interest.

Figures

Figure 1
Figure 1
Relative variation in protein synthesis and degradation rates in clinical and preclinical studies. Variations have been calculated from data reported in quoted references. All data are expressed relative to controls or non‐cachectic cancer patients (indicated by an asterisk).
Figure 2
Figure 2
Comparative analysis of the transcript and protein levels of components of the ubiquitin–proteasome system in cachectic skeletal muscle of cancer patients and animals. Proteins are targeted for degradation by the 26S proteasome through covalent attachment of a chain of ubiquitin molecules. The E1 ubiquitin‐activating enzyme hydrolyses ATP to bind ubiquitin. E2 ubiquitin‐conjugating enzymes receive ubiquitin from E1 and brings it to the E3 ubiquitin‐ligase enzymes, which catalyse the transfer of the ubiquitin from E2 to the substrate. This reaction is the rate‐limiting step of the ubiquitination process. The ubiquitinated protein is then docked to the proteasome for degradation. One gene encodes the E1 enzyme, whereas one hundred genes encode the E2 enzymes and almost one thousand genes the E3 enzymes. Significant variations are reported in red (increase) or blue (decrease). Unchanged levels are reported in white.
Figure 3
Figure 3
Comparative analysis of the regulation of the insulin/IGF1–AKT–mTOR pathway in clinical and preclinical studies. Upon receptor activation, IRS1 promotes the phosphorylation of phosphatidylinositol 4,5‐bisphosphate into phosphatidylinositol 3,4,5‐triphosphate at the plasma membrane by recruiting the kinase PI3K. Phospholipid phosphorylation promotes AKT recruitment and activation by PDK1. AKT positively or negatively regulates multiple targets including mTOR from the mTORC1 complex (not represented) and FOXO transcription factors. AMPK, whose activity is increased by energy stress, is another important modulator of the pathway. Black arrows indicate post‐translational regulation. Red arrows indicate transcriptional regulation. Significant variations are reported in red (increase) or blue (decrease). Unchanged levels are reported in white.
Figure 4
Figure 4
Comparative analysis of the regulation of myostatin/activin A signalling in cachectic skeletal muscle of cancer patients and in animal models of cancer cachexia. Myostatin and activin A bind to activin Type II receptors (ActRIIB/IIA) that activate Type I receptors (ALK4/5/7), which phosphorylate and induce SMAD2/3 to form a complex with SMAD4 and translocate into the nucleus. Myostatin and activin A binding is modulated by the inhibitory action of follistatin. Significant variations are reported in red (increase) or blue (decrease). Unchanged levels are reported in white.
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