Vickie E. Baracos

Multiple types of skeletal muscle atrophy involve a common program of changes in gene expression

Skeletal muscle atrophy is a debilitating response to starvation and many systemic diseases including diabetes, cancer, and renal failure. We had proposed that a common set of transcriptional adaptations underlie the loss of muscle mass in these different states. To test this hypothesis, we used cDNA microarrays to compare the changes in content of specific mRNAs in muscles atrophying from different causes. We compared muscles from fasted mice, from rats with cancer cachexia, streptozotocin‐induced diabetes mellitus, uremia induced by subtotal nephrectomy, and from pair‐fed control rats. Although the content of >90% of mRNAs did not change, including those for the myofibrillar apparatus, we found a common set of genes (termed atrogins) that were induced or suppressed in muscles in these four catabolic states. Among the strongly induced genes were many involved in protein degradation, including polyubiquitins, Ub fusion proteins, the Ub ligases atrogin‐1/MAFbx and MuRF‐1, multiple but not all subunits of the 20S proteasome and its 19S regulator, and cathepsin L. Many genes required for ATP production and late steps in glycolysis were down‐regulated, as were many transcripts for extracellular matrix proteins. Some genes not previously implicated in muscle atrophy were dramatically up‐regulated (lipin, metallothionein, AMP deaminase, RNA helicase‐related protein, TG interacting factor) and several growth‐related mRNAs were down‐regulated (P311, JUN, IGF‐1‐BP5). Thus, different types of muscle atrophy share a common transcriptional program that is activated in many systemic diseases.—Lecker, S. H., Jagoe, R. T., Gilbert, A., Gomes, M., Baracos, V., Bailey, J., Price, S. R., Mitch, W. E., Goldberg, A. L. Multiple types of skeletal muscle atrophy involve a common program of changes in gene expression.—Stewart H. Lecker, R. Thomas Jagoe, Alexander Gilbert, Marcelo Gomes, Vickie Baracos, James Bailey, S. Russ Price, William E. Mitch, Alfred L. Goldberg Multiple types of skeletal muscle atrophy involve a common program of changes in gene expression. FASEB J. 18, 39–51 (2004)

Stimulation of Muscle Protein Degradation and Prostaglandin E2 Release by Leukocytic Pyrogen (Interleukin-1)

To clarify the mechanisms underlying the loss of body protein during fever and sepsis, we incubated rat muscles with highly purified human leukocytic pyrogen. This polypeptide, which appears identical to interleukin-1, is released by leukocytes and signals the onset of fever in the hypothalamus. In muscles incubated at 37 degrees C, leukocytic pyrogen stimulated net protein degradation by 62 to 118 per cent (P less than 0.001). Proteolysis increased, but rates of muscle-protein synthesis did not change. The pyrogen also dramatically stimulated muscle synthesis of prostaglandin E2, which promotes protein breakdown in this tissue. Addition of indomethacin with leukocytic pyrogen prevented prostaglandin E2 synthesis and abolished the increase in proteolysis. The acceleration of protein breakdown induced by pyrogen was also blocked by Ep-475, an inhibitor of lysosomal thiol proteases. When muscles were incubated at 39 degrees C to mimic fever, protein breakdown increased, but addition of leukocytic pyrogen caused a further marked increase in proteolysis and prostaglandin E2 production. Thus, human leukocytic pyrogen can act on skeletal muscle to stimulate intralysosomal proteolysis by increasing the production of prostaglandin E2. These findings suggest that cyclooxygenase inhibitors may be useful in the treatment of negative nitrogen balance in fever. In addition, the release of prostaglandin E2 induced by leukocytic pyrogen may account for the myalgia that accompanies fever.

Cancer Cachexia in the Age of Obesity: Skeletal Muscle Depletion Is a Powerful Prognostic Factor, Independent of Body Mass Index

PURPOSE Emerging evidence suggests muscle depletion predicts survival of patients with cancer. PATIENTS AND METHODS At a cancer center in Alberta, Canada, consecutive patients with cancer (lung or GI; N = 1,473) were assessed at presentation for weight loss history, lumbar skeletal muscle index, and mean muscle attenuation (Hounsfield units) by computed tomography (CT). Univariate and multivariate analyses were conducted. Concordance (c) statistics were used to test predictive accuracy of survival models. RESULTS Body mass index (BMI) distribution was 17% obese, 35% overweight, 36% normal weight, and 12% underweight. Patients in all BMI categories varied widely in weight loss, muscle index, and muscle attenuation. Thresholds defining associations between these three variables and survival were determined using optimal stratification. High weight loss, low muscle index, and low muscle attenuation were independently prognostic of survival. A survival model containing conventional covariates (cancer diagnosis, stage, age, performance status) gave a c statistic of 0.73 (95% CI, 0.67 to 0.79), whereas a model ignoring conventional variables and including only BMI, weight loss, muscle index, and muscle attenuation gave a c statistic of 0.92 (95% CI, 0.88 to 0.95; P < .001). Patients who possessed all three of these poor prognostic variables survived 8.4 months (95% CI, 6.5 to 10.3), regardless of whether they presented as obese, overweight, normal weight, or underweight, in contrast to patients who had none of these features, who survived 28.4 months (95% CI, 24.2 to 32.6; P < .001). CONCLUSION CT images reveal otherwise occult muscle depletion. Patients with cancer who are cachexic by the conventional criterion (involuntary weight loss) and by two additional criteria (muscle depletion and low muscle attenuation) share a poor prognosis, regardless of overall body weight.

Sarcopenia as a Determinant of Chemotherapy Toxicity and Time to Tumor Progression in Metastatic Breast Cancer Patients Receiving Capecitabine Treatment

Purpose: Body composition has emerged as an important prognostic factor in cancer patients. Severe depletion of skeletal muscle (sarcopenia) and, hence, of overall lean body mass may represent an occult condition in individuals with normal or even high body weight. Sarcopenia has been associated with poor performance status, 5-fluorouracil toxicity, and shortened survival in cancer patients. Here, we prospectively studied patients with metastatic breast cancer receiving capecitabine treatment in order to determine if sarcopenia was associated with a higher incidence of toxicity and a shorter time to tumor progression (TTP). Experimental Design: Fifty-five women with metastatic breast cancer resistant to anthracycline and/or taxane treatment were included. Skeletal muscle cross-sectional area at the third lumbar vertebra was measured by computerized tomography, and sarcopenia was defined using a previously published cutoff point. Toxicity was assessed after cycle 1 of treatment, and TTP was determined prospectively. Results: Approximately 25% of patients were classified as sarcopenic, and this feature was seen in normal weight, overweight, and obese individuals. Toxicity was present in 50% of sarcopenic patients, compared with only 20% of nonsarcopenic patients (P = 0.03), and TTP was shorter in sarcopenic patients (101.4 days; confidence interval, 59.8-142.9) versus nonsarcopenic patients (173.3 days; confidence interval, 126.1-220.5; P = 0.05). Conclusion: Sarcopenia is a significant predictor of toxicity and TTP in metastatic breast cancer patients treated with capecitabine. Our results raise the potential use of body composition assessment to predict toxicity and individualize chemotherapy dosing.

Muscle Wasting Is Associated With Mortality in Patients With Cirrhosis

BACKGROUND & AIMS Sarcopenia, defined as a low level of muscle mass, occurs in patients with cirrhosis. We assessed its incidence among cirrhotic patients undergoing evaluation for liver transplantation to investigate associations between sarcopenia and mortality and prognosis. METHODS We studied 112 patients with cirrhosis (78 men; mean age, 54 ± 1 years) who were consecutively evaluated for liver transplantation and had a computed tomography scan at the level of the third lumbar (L3) vertebrae to determine the L3 skeletal muscle index; sarcopenia was defined by using previously published, sex-specific cutoffs. RESULTS Of the patients studied, 45 (40%) had sarcopenia. Univariate Cox analysis associated mortality with ascites (hazard ratio [HR], 2.12; P = .04), encephalopathy (HR, 1.99; P = .04), level of bilirubin (HR, 1.007; P < .01), international normalized ratio (HR, 7.69; P < .001), level of creatinine (HR, 1.01; P = .005), level of albumin (HR, 94; P = .008), serum level of sodium (HR, 89; P < .001), Model for End-Stage Liver Disease (MELD) score (HR, 1.14; P < .01), Child-Pugh score (HR, 2.84; P < .001), and sarcopenia (HR, 2.18; P = .006). By multivariate Cox analysis, only Child-Pugh (HR, 1.85; P = .04) and MELD scores (HR, 1.08; P = .001) and sarcopenia (HR, 2.21; P = .008) were independently associated with mortality. The median survival time for patients with sarcopenia was 19 ± 6 months, compared with 34 ± 11 months among nonsarcopenia patients (P = .005). There was a low level of correlation between L3 skeletal muscle index and MELD (r = -0.07; P = .5) and Child-Pugh scores (r = -0.14; P = .1). CONCLUSIONS Sarcopenia is associated with mortality in patients with cirrhosis. It does not correlate with the degree of liver dysfunction evaluated by using conventional scoring systems. Scoring systems should include evaluation of sarcopenia to better assess mortality among patients with cirrhosis.

Sarcopenia is associated with postoperative infection and delayed recovery from colorectal cancer resection surgery

Background:Skeletal muscle depletion (sarcopenia) predicts morbidity and mortality in the elderly and cancer patients.Methods:We tested whether sarcopenia predicts primary colorectal cancer resection outcomes in stage II–IV patients (n=234). Sarcopenia was assessed using preoperative computed tomography images. Administrative hospitalisation data encompassing the index surgical admission, direct transfers for inpatient rehabilitation care and hospital re-admissions within 30 days was searched for International Classification of Disease (ICD)-10 codes for postoperative infections and inpatient rehabilitation care and used to calculate length of stay (LOS).Results:Overall, 38.9% were sarcopenic; 16.7% had an infection and 9.0% had inpatient rehabilitation care. Length of stay was longer for sarcopenic patients overall (15.9±14.2 days vs 12.3±9.8 days, P=0.038) and especially in those ⩾65 years (20.2±16.9 days vs 13.1±8.3 days, P=0.008). Infection risk was greater for sarcopenic patients overall (23.7% vs 12.5%; P=0.025), and especially those ⩾65 years (29.6% vs 8.8%, P=0.005). Most (90%) inpatient rehabilitation care was in patients ⩾65 years. Inpatient rehabilitation was more common in sarcopenic patients overall (14.3% vs 5.6%; P=0.024) and those ⩾65 years (24.1% vs 10.7%, P=0.06). In a multivariate model in patients ⩾65 years, sarcopenia was an independent predictor of both infection (odds ratio (OR) 4.6, (95% confidence interval (CI) 1.5, 13.9) P<0.01) and rehabilitation care (OR 3.1 (95% CI 1.04, 9.4) P<0.04).Conclusion:Sarcopenia predicts postoperative infections, inpatient rehabilitation care and consequently a longer LOS.

Body Composition as an Independent Determinant of 5-Fluorouracil–Based Chemotherapy Toxicity

Purpose: Evidence suggests that lean body mass (LBM) may be useful to normalize doses of chemotherapy. Data from a prospective study were used to determine if the highest doses of 5-fluorouracil (5-FU) per kilogram LBM would be associated with dose-limiting toxicity in stage II/III colon cancer patients treated with 5-FU and leucovorin. Experimental Design: Toxicity after cycle 1 was graded according to National Cancer Institute Common Toxicity Criteria, version 2.0. Muscle tissue was measured by computerized tomography. An extrapolation to the LBM compartment of the whole body was employed. Results: Mean values of 5-FU/LBM of the entire population were different in terms of presence or absence of toxicity (P = 0.036). A cut point of 20 mg 5-FU/kg LBM seemed to be a threshold for developing toxicity (P = 0.005). This observation was pertinent to women (odds ratio, 16.73; P = 0.021). Women in this study had a relatively low proportion of LBM relative to their body surface area. Conclusion: Our study shows that low LBM is a significant predictor of toxicity in female patients administered 5-FU using the convention of dosing per unit of body surface area. We conclude that variation in toxicity between females and males may be partially explained by this feature of body composition.

Low body mass index and sarcopenia associated with dose-limiting toxicity of sorafenib in patients with renal cell carcinoma

BACKGROUND Patients with severe depletion of skeletal muscle (sarcopenia) are prone to dose-limiting toxicity (DLT) during fluoropyrimidine therapy. We hypothesized that sarcopenia may also predict toxicity of targeted therapy drugs. MATERIALS AND METHODS Metastatic renal cell cancer (RCC) patients (n = 55) received sorafenib 400 mg b.i.d. Weight, height and skeletal muscle cross-sectional area at the third lumbar vertebra were measured by computed tomography (CT). Toxicity was assessed. RESULTS DLT occurred in 22% of patients overall, of which three-quarters were dose reductions to 400 mg and the remainder entailed termination of treatment. DLT was most common (41%) in sarcopenic patients whose body mass index (BMI) was <25 kg/m(2) and least common (13%) in patients who were not sarcopenic and/or overweight or obese (P = 0.03). Toxicity was especially prevalent in sarcopenic male patients with BMI < 25, with 71% of men with these characteristics being unable to continue treatment at 800 mg/day. By contrast, only 5% of male patients whose muscle index was above the cut-off for sarcopenia and only 11% of male patients whose BMI was >25 experienced a DLT. CONCLUSION BMI < 25 kg/m(2) with diminished muscle mass is a significant predictor of toxicity in metastatic RCC patients treated with sorafenib.

Body composition in patients with non–small cell lung cancer: a contemporary view of cancer cachexia with the use of computed tomography image analysis

BACKGROUND The prominent clinical feature of cachexia has traditionally been understood to be weight loss; however, in recognition of the potential for divergent behavior of muscle and adipose tissue, cachexia was recently defined as loss of muscle with or without loss of fat mass. Detailed assessments are required to verify body composition in patients with cancer cachexia. DESIGN We adopted a population-based approach to study body composition in patients with cancer, with the use of diagnostic computed tomography images acquired for cancer diagnosis and follow-up. A prospective cohort of 441 patients with non-small cell lung cancer, who were referred consecutively to a regional medical oncology service in Alberta, Canada, was evaluated. RESULTS At referral (median time to death: 265 d), mean body mass index (BMI; in kg/m(2)) was 24.9, with 47.4% of patients being overweight or obese. Only 7.5% overall were underweight as conventionally understood (BMI < 18.5). Analysis of computed tomography images showed extremely high heterogeneity of muscle mass within all strata of BMI. The overall prevalence of severe muscle depletion (sarcopenia) was 46.8% and was present in patients in all BMI categories. A much higher proportion of men (61%) than women (31%) met the criteria for sarcopenia. CONCLUSIONS Wasting of skeletal muscle is a prominent feature of patients with lung cancer, despite normal or heavy body weights. The significance of muscle wasting in normal-weight, overweight, and obese patients as a nutritional risk factor, as a prognostic factor, and as a predictor of cancer treatment toxicity is discussed in this article.

Understanding and managing cancer cachexia

Mrs MJ is a 56-year-old architect with a husband and two children. You performed a mastectomy and axillary dissection on her after neoadjuvant chemotherapy for locally advanced breast cancer 2 years ago. Unfortunately, she developed widespread disease with metastases to liver, lung, and bone. After several more rounds of chemotherapy, she is currently on antiestrogen therapy. Her disease appears stable. You have continued to follow her and she comes to see you for her routine visit. You notice that she is much thinner than you remember, but otherwise looks well. You ask her about her weight loss. She says: “I don’t really know what it is! I can eat, my bowels are working, but I simply don’t want to. I force myself to swallow food, but I keep losing weight anyway.” On clinical examination, you notice her muscle wasting and recognize the signs of cancer cachexia. You want to know more about how to manage this phenomenon.