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Review Mechanisms of Skeletal Muscle Degradation and Its Therapy in Cancer Cachexia

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Review Mechanisms of Skeletal Muscle Degradation and Its Therapy in Cancer Cachexia Histol Histopathol (2007) 22: 805-814 Histology and http://www.hh.um.es Histopathology Cellular and Molecular Biology Review Mechanisms of skeletal muscle degradation and its therapy in cancer cachexia L.G. Melstrom1, K.A. Melstrom Jr.2, X.-Z. Ding1 and T.E. Adrian1,3 1Department of Surgery and Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, 2Department of Surgery, Loyola University Medical Center, Maywood, Illinois and 3Department of Physiology, United Arab Emirates University, Faculty of Medicine and Health Sciences, Al Ain, UAE Summary. Severe or chronic disease can lead to Introduction cachexia which involves weight loss and muscle wasting. Cancer cachexia contributes significantly to Cachexia can be described as weight loss, muscle disease morbidity and mortality. Multiple studies have wasting, loss of appetite and general debility occurring shown that the metabolic changes that occur with cancer with a chronic disease. This condition can be seen in cachexia are unique compared to that of starvation. patients with acquired immune deficiency syndrome, Specifically, cancer patients seem to lose a larger sepsis, renal failure, burns, trauma and cancer. Cachexia proportion of skeletal muscle mass. There are three is present in up to 50% of cancer patients and accounts pathways that contribute to muscle protein degradation: for at least 30% of cancer-related deaths overall (Palesty the lysosomal system, cytosolic proteases and the and Dudrick, 2003). The wasting of respiratory muscles ubiquitin (Ub)-proteasome pathway. The Ub-proteasome eventually causes these patients to succumb to pathway seems to account for the majority of skeletal pneumonia (Windsor and Hill, 1988). muscle degradation in cancer cachexia and is stimulated The body composition changes that occur with by several cytokines including tumor necrosis factor-α, cancer cachexia are unique compared to those for interleukin-1ß, interleukin-6, interferon-γ and starvation. For equivalent amounts of weight loss, there proteolysis-inducing factor. is a greater degree of muscle mass lost in cancer Cachexia is particularly severe in pancreatic cancer cachexia (Heymsfield and McManus, 1985). In patients and contributes significantly to the quality of life and with anorexia, the majority of weight lost is from fat, mortality of these patients. Several factors contribute to whereas lung cancer patients who had lost 30% of their weight loss in these patients, including alimentary baseline weight, demonstrated an 85% decrease in total obstruction, pain, depression, side effects of therapy and body fat and a 75% decrease in skeletal muscle protein a high catabolic state. Although no single agent has mass (Fearon, 1992; Moley et al., 1987). This proven to halt cachexia in these patients there has been demonstrates that both fat stores and muscle stores are some progress in the areas of nutrition with significantly reduced in cancer cachexia. There is also a supplementation and pharmacological agents such as preferential loss of skeletal muscle versus visceral organ megesterol acetate, steroids and experimental trials muscle in response to acidosis, infection or cancer targeting cytokines that stimulate the Ub-proteasome (Mitch and Goldberg, 1996). Baracos et al. demonstrated pathway. that rats implanted with Yoshida ascites hepatoma (YAH), showed a rapid and selective loss of skeletal Key words: Cancer cachexia, Skeletal muscle muscle protein due mainly to a marked increase (63- degradation 95%) in the rate of protein degradation (Baracos et al., 1995). However, in this study there was no change in weight or mRNA content of liver, kidney, heart or brain. Skeletal muscle protein catabolism Offprint requests to: Thomas E. Adrian, Professor and Chairman, Department of Physiology, United Arab Emirates University, Faculty of Muscle protein degradation occurs through three Medicine and Health Sciences, PO Box 17666, Al Ain, UAE. e-mail: pathways: the lysosomal system, a group of calcium [email protected] activated cytosolic proteases, and the ubiquitin (Ub)- 806 Skeletal muscle in cancer cachexia proteasome pathway (Lecker et al., 1999). The three specific proteolytic actions: “chymotrypsin-like,” lysosomal system accounts for the degradation of “trypsin-like,” and cleavage after acidic residues making endocytosed proteins and phagocytosed bacteria. it “caspase-like”(Tisdale, 2005). Once proteins are Lysosomes contain several acid optimal proteases such processed, short oligopeptides comprised of six to nine as cathepsins B, H, and D. Lysosomal degradation of amino acid residues are released and further degraded proteins is accelerated by glucagon in the liver and the into tripeptides by tripeptidlypeptidase II and then into lack of insulin or essential amino acids (Gronostajski et single amino acids by aminopeptidases. It is important to al., 1984). The use of lysosomal protease and understand the components of the ubiquitin-proteasome acidification inhibitors demonstrated that the lysosomal pathway as they are key targets in regulating the skeletal pathway is mostly to degrade surface membrane proteins muscle degradation seen in cancer cachexia. and endocytosed, extracellular proteins rather than influencing the normal turnover of cytosolic proteins The ubiquitin-proteosome pathway in catabolic (Furano and Goldberg, 1986; Lowell et al., 1986). The states second pathway for protein degradation is via calpains which are calcium activated cytosolic cysteine proteases. The function of the ubiquitin-proteasome pathway is These proteases are ATP-independent and are activated to degrade defective protein products produced from by an increase in cytosolic calcium, indicating that they errors in translation or from oxidative stress (Schubert et are important in tissue injury, necrosis and autolysis al., 2000; Tisdale, 2005). This pathway is activated in (Murachi et al., 1980; Waxman, 1981; Mellgren, 1987; catabolic states resulting in muscle atrophy. Studies of in Gikk et al., 1992). The ATP-ubiquitin dependent vitro atrophying muscles have demonstrated that proteolytic pathway which is responsible for the inhibition of lysosomal proteases or calcium-activated majority of skeletal muscle protein catabolism (Lecker et proteases does not change the rate of proteolysis. al., 1999). This pathway likely accounts for the However, with inhibitors of ATP production, the rate of advanced proteolysis seen in wasting conditions such as proteolysis decreases to that of control muscles, fasting, sepsis, metabolic acidosis, acute diabetes, indicating that the ATP-dependent Ub-proteasome weightlessness and cancer cachexia (Goll et al., 1992). pathway is primarily responsible for skeletal muscle degradation (Wing and Goldberg, 1993; Mitch et al., The Ub-Proteasome Pathway 1994). Muscle protein degradation in Yoshida Ascites Hepatoma (YAH) bearing rats was not inhibited by the Most cellular proteins are degraded by the ATP- removal of calcium or by blocking the calcium- dependent Ub-proteasome pathway. This entails proteins dependent proteolytic system. The inhibition of being identified for degradation by the addition of lysosomal function reduced proteolysis by 12% in multiple ubiquitin molecules and subsequent recognition muscles from YAH tumor-bearing rats. However, when and degradation by the 26S proteasome. Proteins are ATP production was inhibited, the remaining accelerated initially marked for degradation by binding ubiquitin, a proteolysis in muscles of tumor-bearing rats fell to that small protein cofactor (Mitch and Goldberg, 1996). of control levels. This study also revealed that while Ubiquitin is activated by an activating enzyme (E1) in a muscles of YAH-bearing rats showed a total decrease in two step process. Firstly, an intermediate is formed by total RNA content (by 20-30%), there was a significant ATP hydrolysis connecting adenosine monophosphate increase in ubiquitin mRNA (590-880%), the level of (AMP) with the carboxy-terminal carboxyl group of ubiquitin-conjugated proteins, and of mRNA for glycine in ubiquitin. This then forms a thioester linkage multiple proteosome subunits (100-215%) (Baracos et with a cysteine residue in E1 (Tisdale, 2005). The al., 1995). These studies support the concept that ubiquitin carrier protein (E2) then accepts this ubiquitin accelerated muscle proteolysis is primarily due to the to its active site at a cysteine residue. Next, the E2 activation of the ATP-dependent pathway. In addition, at carrier protein recognizes the Ub protein ligase (E3). least three specific E3 ubiquitin ligases have been The E3 ligase transfers ubiquitin from the E2 thioester identified. The E3αII ligase has been shown to be more intermediate either to a specific ubiquitin binding site or specifically expressed in muscle tissues and is also to an isopeptide linkage with some degree of substrate differentially activated by the cytokines tumor necrosis specificity (Lecker et al., 1999). Multiple rounds of E3 factor-α (TNF-α) and interleukin-6 (IL-6) (Beutler and ubiquitin ligation create a polyubiquitin chain on the Cerami, 1988; Matthys and Billiau, 1997; Moldawer and substrate. Copeland, 1997; Tisdale, 2002; Kwak et al., 2004). Once the proteins are marked with a polyubiquitin chain, they are degraded into oligopeptides by the 26S Stimulators of the ubiquitin proteasome pathway in proteasome. This molecule is comprised of a 20S catabolic states proteasome in the center with a 19S particle on each end. The
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