Skeletal muscle proteome expression differentiates severity of cancer cachexia in mice and identifies loss of fragile X mental retardation syndrome‐related protein 1

Abstract

Tandem mass tag (TMT)‐based quantitative proteomics was used to examine protein expression in skeletal muscle from mice with moderate and severe cancer cachexia to study mechanisms underlying varied cachexia severity. Weight loss of 10% (moderate) and 20% (severe) was induced by injection of colon‐26 cancer cells in 10‐week old Balb/c mice. In moderate cachexia, enriched pathways reflected fibrin formation, integrin/mitogen‐activated protein kinase (MAPK) signaling, and innate immune system, suggesting an acute phase response and fibrosis. These pathways remained enriched in severe cachexia; however, energy‐yielding pathways housed in mitochondria were prominent additions to the severe state. These enrichments suggest distinct muscle proteome expression patterns that differentiate cachexia severity. When analyzed with two other mouse models, eight differentially expressed targets were shared including serine protease inhibitor A3N (Serpina3n), synaptophysin‐like protein 2 (Sypl2), Isocitrate dehydrogenase [NAD] subunit alpha, mitochondrial (Idh3a), peroxisomal acyl‐coenzyme A oxidase 1 (Acox1), collagen alpha‐1(VI) chain (Col6a1), myozenin 3 (Myoz3), UDP‐glucose pyrophosphorylase (Ugp2), and solute carrier family 41 member 3 (Slc41a3). Acox1 and Idh3a control lipid oxidation and NADH generation in the TCA cycle, respectively, and Col6a1 comprises part of type VI collagen with reported profibrotic functions, suggesting influential roles in cachexia. A potential target was identified in fragile X mental retardation syndrome‐related protein 1 (FXR1), an RNA‐binding protein not previously implicated in cancer cachexia. FXR1 decreased in cachexia and related linearly with weight change and myofiber size. These findings suggest distinct mechanisms associated with cachexia severity and potential biomarkers and therapeutic targets.

Skeletal Muscle Proteome Modifications following Antibiotic-Induced Microbial Disturbances in Cancer Cachexia

“…Regarding the effect of cachexia, we quantified only 12 differentially accumulated proteins between the CT and C26 groups (Table ). Several studies have described skeletal muscle proteome changes induced by cancer cachexia in different models presenting a subcutaneous implantation of colon carcinoma cell lines (C26 cells), afflicted with various profiles of cachexia severity, ,, Some proteins identified in our study, such as haptoglobin, hemopexin, C3, and serum amyloid P-component, are involved in the innate immune response and are biomarkers identified in previous works. , We also found a biomarker named CACNA1S (voltage-dependent L-type calcium channel subunit alpha) that has been identified in a moderate form of cachexia . This protein, expressed in skeletal muscle, is the pore-forming subunit of the dihydropyridine receptor (DHPR) and is coupled to the Ryanodine receptor Ca2+-release channel-1 (RYR1) during muscle excitation and contraction .…”

“…Several studies have described muscle proteome alterations induced by cancer cachexia, ,, but our study is the first to explore the proteome profile changes induced by antibiotics-induced microbial disturbances outside and in the C26 mouse model. To better understand how microbial disturbance affects muscle metabolism in cancer cachexia, a shotgun protein analysis was performed on the gastrocnemius muscle of the CT, C26, CT-ATB, and C26-ATB mice groups.…”

“…Anabolic signaling pathways implicating Insulin Growth Factor 1 (IGF1) and mammalian Target of Rapamycin (mTOR) are also impaired, leading to a decrease in the skeletal muscle protein synthesis rate . In addition to the global investigation of skeletal muscle protein metabolism regulation, some studies based on the exploration of skeletal muscle protein expressions through a proteomic approach have highlighted metabolic pathways that could be affected during cancer cachexia . For instance, proteomic analyses in the quadriceps of mice with severe cachexia revealed that two-thirds of the proteins identified were downregulated and involved in muscle energy metabolism, more specifically mitochondrial function (the tricarboxylic acid or TCA cycle, mitochondrial respiratory chain, glycolysis, and fatty acid beta oxidation) .…”

“…In a rodent model of cancer cachexia, the Colon-26 Carcinoma Tumor-bearing mouse (the C26 mouse), proteomic analyses of skeletal muscle showed an upregulation of acute phase reaction proteins and complement responses, and a downregulation of proteins involved in mitochondria oxidative phosphorylation as well as ribosomal proteins . Finally, skeletal muscle proteomic analyses in C26 mice with moderate (10% weight loss) and severe (20% weight loss) cachexia revealed altered pathways such as extracellular matrix regulation and fibrin formation, Mitogen activated protein kinase (MAPK) signaling, inflammatory response (via Toll Like Receptor or TLR regulation and complement signaling), and ribosome and translation pathways . Several pathways were identified in severe cachexia, including mitochondrial metabolic alterations (TCA cycle, mitochondrial electron transport, and pyruvate metabolism).…”

Space Omics and Tissue Response in Astronaut Skeletal Muscle after Short and Long Duration Missions

“…Altered calcium signaling key protein levels following SDM spaceflight found in this work thus highlights maladaptation of the mostly slow-twitched muscle fiber (type I) containing SOL (expressing both CASQ1 and 2) where an increase in CASQ1 and CASQ2 and two other related proteins (ANXA2, ATP2A1) was detected at variance in both SDM and LDM samples, suggesting (Ca 2+ )-binding proteins as a protein hub to acute microgravity exposition of human muscle (SOL) in spaceflight. The reduction in muscular synaptophysin-like protein 2 (SYPL2), a presynaptic biomarker, recently shown to be important for cachectic mice [ 33 ] but also found in an SDM muscle sample compared to LDM, suggests an altered transverse (t)-tubules/sarcoplasmic membrane terminal cisternae communication as a likely early event possibly affected during exposure to µG. Further investigations, however, are required to further support such hypothesis.…”