Cancer-induced muscle atrophy is determined by intrinsic muscle oxidative capacity.

We tested the hypothesis that cancer cachexia progression would induce oxidative post-translational modifications (Ox-PTMs) associated with skeletal muscle wasting, with different responses in muscles with the prevalence of glycolytic and oxidative fibers. We used cysteine-specific isotopic coded affinity tags (OxICAT) and gel-free mass spectrometry analysis to investigate the cysteine Ox-PTMs profile in the proteome of both plantaris (glycolytic) and soleus (oxidative) muscles in tumor-bearing and control rats. Histological analysis revealed muscle atrophy in type II fibers in plantaris muscle, with no changes in plantaris type I fibers and no differences in both soleus type I and II fibers in tumor-bearing rats when compared to healthy controls. Tumor progression altered the Ox-PTMs profile in both plantaris and soleus. However, pathway analysis including the differentially oxidized proteins revealed tricarboxylic acid cycle and oxidative phosphorylation as main affected pathways in plantaris muscle from tumor-bearing rats, while the same analysis did not show main metabolic pathways affected in the soleus muscle. In addition, cancer progression affected several metabolic parameters such as ATP levels and markers of oxidative stress associated with muscle atrophy in plantaris muscle, but not in soleus. However, isolated soleus from tumor-bearing rats had a reduced force production capacity when compared to controls. These novel findings demonstrate that tumor-bearing rats have severe muscle atrophy exclusively in glycolytic fibers. Cancer progression is associated with cysteine Ox-PTMs in the skeletal muscle, but these modifications affect different pathways in a glycolytic muscle compared to an oxidative muscle, indicating that intrinsic muscle oxidative capacity determines the response to cancer cachectic effects.

Serum Creatinine as a Potential Biomarker of Skeletal Muscle Atrophy in Non-small Cell Lung Cancer Patients.

Objectives: Identifying simple biomarkers to determine muscle atrophy in non-small-cell lung cancer (NSCLC) patients remains a critical research gap. Since creatinine is mainly a product from intramuscular creatine metabolism, we tested the hypothesis that low serum creatinine levels would be associated to skeletal muscle atrophy in NSCLC patients. Materials and Methods: This is a prospective cohort study including 106 treatment-naive patients with histologically confirmed stage IV NSCLC. All patients performed routine serum creatinine laboratory tests. We divided patients into two groups based on low (<0.7 mg/dL for male and <0.5 mg/dL for female) or normal creatinine levels. We compared body mass index (BMI), psoas muscle cross-sectional area, adipose tissue area and complete blood counts between groups. Results: Male and female NSCLC patients with low serum creatinine levels had low muscle cross-sectional area as compared to patients with normal serum creatinine levels. Male NSCLC patients with low serum creatinine also displayed reduced BMI, reduced adipose tissue area, and elevated systemic inflammation compared to NSCLC patients with normal serum creatinine levels. There were no significant differences between female groups for BMI, adipose tissue area and inflammatory markers. Conclusions: Serum creatinine is a potential prognostic biomarker of skeletal muscle atrophy in NSCLC patients. Since serum creatinine is a simple and accessible measurement, we suggest that it should be monitored in longitudinal follow-up of NSCLC patients as a biomarker of muscle atrophy.

Exercise-Induced Increases in Insulin Sensitivity After Bariatric Surgery Are Mediated By Muscle Extracellular Matrix Remodeling.

Exercise seems to enhance the beneficial effect of bariatric (Roux-en-Y gastric bypass [RYGB]) surgery on insulin resistance. We hypothesized that skeletal muscle extracellular matrix (ECM) remodeling may underlie these benefits. Women were randomized to either a combined aerobic and resistance exercise training program following RYGB (RYGB + ET) or standard of care (RYGB). Insulin sensitivity was assessed by oral glucose tolerance test. Muscle biopsy specimens were obtained at baseline and 3 and 9 months after surgery and subjected to comprehensive phenotyping, transcriptome profiling, molecular pathway identification, and validation in vitro. Exercise training improved insulin sensitivity beyond surgery alone (e.g., Matsuda index: RYGB 123% vs. RYGB + ET 325%; P ≤ 0.0001). ECM remodeling was reduced by surgery alone, with an additive benefit of surgery and exercise training (e.g., collagen I: RYGB -41% vs. RYGB + ET -76%; P ≤ 0.0001). Exercise and RYGB had an additive effect on enhancing insulin sensitivity, but surgery alone did not resolve insulin resistance and ECM remodeling. We identified candidates modulated by exercise training that may become therapeutic targets for treating insulin resistance, in particular, the transforming growth factor-ß1/SMAD 2/3 pathway and its antagonist follistatin. Exercise-induced increases in insulin sensitivity after bariatric surgery are at least partially mediated by muscle ECM remodeling.

18F-Fluoride PET/CT and 99mTc-MDP SPECT/CT can detect bone cancer at early stage in rodents.

Noninvasive imaging using positron emission tomography/computed tomography (PET/CT) and single photon emission computed tomography/computed tomography (SPECT/CT) are considered revolutionized approaches to detect bone cancer. Both PET/CT and SPECT/CT technologies have advanced to permit miniaturization, which has provided the advantage of including animals as their own controls in longitudinal studies. The present study was designed to evaluate the potential of PET/CT and SPECT/CT as research tools to detect bone cancer in rats. We used a rat model of bone cancer induced by injecting Walker 256 tumor cells into the femoral cavity. Computed tomography demonstrated that rats presented a solid tumor at 15 days post injection (dpi). However, CT was not an effective method for identifying tumors at an earlier time point (8 dpi), when mechanical hyperalgesia (the most common symptom during bone cancer progression) had already initiated. At this early stage, PET/CT and SPECT/CT analysis detected higher uptake in the injected femur of the tracers 18F-Fluoride and 99mTc-Methyl diphosphonate (99mTc-MDP), respectively. These findings demonstrated for the first time that both 18F-Fluoride PET/CT and 99mTc-MDP SPECT/CT can detect cancer at early stages in rats and advocates for the PET/SPECT/CT as research tools to evaluate bone cancer in further longitudinal studies involving small animals.

Loss of strength capacity is associated with mortality, but resistance exercise training promotes only modest effects during cachexia progression.

AIMS: Resistance exercise training (RET) has been adopted as non-pharmacological anti-catabolic strategy. However, the role of RET to counteract cancer cachexia is still speculative. This study aimed to verify whether short-term RET would counteract skeletal muscle wasting in a severe cancer cachexia rat model. MAIN METHODS: Wistar rats were randomly allocated into four experimental groups; 1) untrained control rats (control), 2) rats submitted to RET (control+RET), 3) untrained rats injected with Walker 256 tumor cells in the bone marrow (tumor) and 4) rats injected with Walker 256 tumor cells in the bone marrow and submitted to RET (tumor+RET). KEY FINDINGS: Tumor group displayed skeletal muscle atrophy fifteen days post tumor cells injection as assessed by plantaris (-20.5%) and EDL (-20.0%) muscle mass. EDL atrophy was confirmed showing 43.8% decline in the fiber cross sectional area. Even though RET increased the lactate dehydrogenase protein content and fully restored phosphorylated form of 4EBP-1 to the control levels in skeletal muscle, it failed to rescue muscle morphology in tumor-bearing rats. Indeed, RET did not mitigated loss of muscle function, anorexia, tumor growth or mortality rate. However, loss of strength capacity (assessed by 1-RM test performance) demonstrated a negative correlation with rats' survival (p=0.02; r=0.40), suggesting that loss of strength capacity might predict cancer mortality. SIGNIFICANCE: These results demonstrated that bone marrow injection of Walker 256 tumor cells in rats induces cancer cachexia, strength capacity is associated with cancer survival and short-term RET promotes only modest effects during cachexia progression.

An overview of amines as nutritional supplements to counteract cancer cachexia.

Cancer cachexia is a complex multifactorial syndrome characterized by loss of skeletal muscle mass (with or without loss of fat mass) that cannot be fully reversed by conventional nutritional support and leads to progressive functional impairment. Recently, some amino acids and other amine dietary supplements have been highlighted in medical field due to positive effects upon diseases evolving skeletal muscle atrophy. Therefore, the aim of this brief review is to discuss the putative application of amines as dietary supplements to counteract skeletal muscle wasting on cancer cachexia. Specifically, we focus in two nutritional supplements: (1) branched-chain amino acids (BCAAs) and (2) creatine. Both BCAAs and creatine may attenuate proteolysis and enhance proteins synthesis in skeletal muscle. Although more experimental studies and clinical trials are still necessary to elucidate this therapeutic application, several evidences have demonstrated that amines supplementation is a promising coadjuvant treatment to cancer cachexia.