Two main pathways induce protein degradation in cancer cachexia: UPS and autophagy [2]. UPS requires enzymes called E1, E2, and E3 to be activated and docked to a protein that will be degraded. E3 binds to a specific protein that soon will be docked to ubiquitin and transported to the proteasome. Two kinds of E3 have been recognized to be involved in muscle atrophy: MuRF1 and Atrogin-1. The skeletal muscles in cancer cachexia also expressed MuRF1 and Atrogin-1, which activate E3 enzymes, thus stimulating UPS pathways [33]. Autophagy also occurs through the process of engulfing ubiquitinated proteins via phagosomes and fusing them with a lysosome [34].

Hentilä et al. reported higher levels of lipidated LC3, LC3II/LC3I ratio, LC3b mRNA, and Beclin-1 in the skeletal muscle of C26 tumor-bearing mice. These findings were followed by increased p62 protein and unchanged p62 mRNA levels, suggesting a reduction in autophagosome clearance. These findings imply that autophagy, in conjunction with the UPS, leads to muscle atrophy [35]. Penna et al. measured the level of autophagy in the gastrocnemius muscle of C26 tumor-bearing mice and found that the levels of microtubule-associated protein 1 light chain 3B isoform I (LC3BI) remained unchanged, although the lipidated form (LC3BII) dramatically increased. Beclin-1, a key upstream regulator of autophagic sequestration, was significantly higher, implying that autophagy activation is a key to the early event in tumor-induced muscle depletion; p62 accumulated in a similar manner to Beclin-1 and LC3BII, which could indicate either the induction of autophagic sequestration or reduced autophagosome clearance [32].

In addition to skeletal muscle atrophy, cardiac remodeling is also induced by cancer cachexia, causing a condition known as cardiac cachexia [34,36]. Cancer cachexia might also induce cardiac remodeling that might disturb cardiac function, which is characterized by microscopic changes displaying cardiac atrophy because of the progressive loss of cardiac muscles [36,37].

The molecular mechanism underlying cardiac muscle atrophy is slightly different from the one that induces skeletal muscle atrophy in cancer cachexia [34,38]. Some studies showed an increase of UPS in the cachectic heart, although another study demonstrated that UPS did not increase, while autophagy did [38,39,40,41]. Cancer-induced cachexia implies a nutrient imbalance and cytokine production that affect cardiac muscle gene expression, causing an imbalance in cellular metabolism, inflammation, and necrosis [42]. In such conditions, cardiac muscles express transforming growth factor (TGF) and BNIP3, which induce autophagy, and then necrosis and fibrosis development [20]. Other markers, such as TRAF6, which is involved in apoptosis, and Beclin-1, which induces autophagy, are increased in cardiac muscle undergoing remodeling [34].

Cosper and Leinwand proved that the proteins of cathepsin L, Beclin, and LC3 were increased during cardiomyocyte atrophy in cancer, suggesting increased autophagy. They found a two-fold increase of cathepsin L mRNA in both male and female atrophic hearts, a 1.5-fold increase of LC3 mRNA, and a seven-fold increase of LC3II protein levels in male atrophic hearts, but only a three-fold increase in females [39]. Another study found a decrease of cardiac mass in the ApcMin/+ mouse model of colorectal cancer, together with an increase of Beclin-1 protein level, without a change of ubiquitination or apoptosis protein in the cardiac tissue. This result showed an increased autophagy process in cardiac cachexia, with no change of UPS stimulation and apoptosis [43].

Liver metabolism is also affected by cachexia via insufficient energy expenditure, phosphorylation oxidation, and lipid metabolism. The liver in cancer cachexia undergoes energy wasting by employing metabolic futile cycles that dissipate energy without anabolic or catabolic function [44]. Tumor cells induce the liver to produce energy via gluconeogenesis of lactate that is derived. The lactate is produced by tumor cells through aerobic glycolysis, known as the “Warburg effect” [45,46]. The liver also releases acute-phase proteins that alleviate inflammation and increase muscle protein breakdown [47,48]. Amino acids produced by skeletal muscle protein degradation provide further gluconeogenesis in the liver [44]. Energy wasting in cancer cachexia also decreases the phosphorylation oxidation capacity in mitochondria, which is marked by an increase of cardiolipin mediated by TNFα [49,50]. Recent research also showed that mitochondrial quality control (mitophagy and fission) was altered in cancer cachexia, in line with the development of hepatic fibrosis [51]. The liver cells in patients with cachexia have a decreased capability to distribute fat via very low-density lipoprotein (VLDL), along with an inability to oxidize fat production and deposition in liver cells, thus leading to liver steatosis [48]. These changes in liver metabolism are correlated with autophagy function, especially lipid droplet clearance, damaged mitochondria, protein aggregate removal, and liver fibrosis prevention [52]. Previous research strongly demonstrated that autophagy is critical to liver function, with lower autophagy linked to poorer results [53,54,55].

Rosa-Caldwell et al. showed that there was no link between the Beclin mRNA content and cancer progression. It was also observed that the LC3II/LC3I ratio, which acted as a surrogate measure of autophagosome production, showed a quadratic connection with cancer progression, with a 40–50% decrease in the LC3II/LC3I ratio at weeks one, two, and three, subsequently increasing at week four. The level of p62 mRNA did not change between the cancer groups, whereas the level of p62 protein increased over time as the disease progressed. In addition, it was also found that mitophagy and fission are altered before hepatic fibrosis occurs [51]. Another study found that the level of LC3II and the LC3II/LC3I ratio, as well as Beclin-1, increased in the liver of C26 tumor-bearing animals. In contrast to the skeletal muscle, an animal model of C26 colon cancer only showed elevated LC3I in the liver, with no change in p62, suggesting increased autophagosome formation without increased or decreased autophagic flux [35].