Investigation of Raman Spectroscopic Signatures with Multivariate Statistics: An Approach for Cataloguing Microbial Biosignatures.

Spectroscopic instruments are increasingly being implemented in the search for extraterrestrial life. However, microstructural spectral analyses of alien environments could prove difficult without knowledge on the molecular identification of individual spectral signatures. To bridge this gap, we introduce unsupervised K-means clustering as a statistical approach to discern spectral patterns of biosignatures without prior knowledge of spectral regions of biomolecules. Spectral profiles of bacterial isolates from analogous polar ice sheets were measured with Raman spectroscopy. Raman analysis identified carotenoid and violacein pigments, and key cellular features including saturated and unsaturated fats, triacylglycerols, and proteins. Principal component analysis and targeted spectra integration biplot analysis revealed that the clustering of bacterial isolates was attributed to spectral biosignatures influenced by carotenoid pigments and ratio of unsaturated/saturated fat peaks. Unsupervised K-means clustering highlighted the prevalence of the corresponding spectral peaks, while subsequent supervised permutational multivariate analysis of variance provided statistical validation for spectral differences associated with the identified cellular features. Establishing a validated catalog of spectral signatures of analogous biotic and abiotic materials, in combination with targeted supervised tools, could prove effective at identifying extant biosignatures.

Response of barren-ground caribou to advancing spring phenology.

Phenological shifts are occurring in many ecosystems around the world. The capacity of species to adapt to changing phenology will be critical to their success under climate change scenarios. Failure to adjust migratory and reproductive timing to keep pace with the earlier onset of spring has led to negative demographic effects for populations of species across a variety of taxa. For caribou, there have been concerns that earlier spring green-up on calving areas might not be matched by earlier migration and parturition, potentially leading to a trophic mismatch with nutritional consequences for parturient and lactating caribou cows. However, there is limited evidence supporting these concerns. Here, we investigate the response of barren-ground caribou to changing spring phenology using data from telemetry and satellite imagery. From 2004 to 2016, we found that the average start of green-up on the calving area advanced by 7.25 days, while the start of migration advanced by 13.64 days, the end of migration advanced by 6.02 days, and the date of peak calving advanced by 9.42 days. Despite the advancing onset of green-up, we found no evidence for the development of a trophic mismatch because the advancing green-up coincided with earlier migration and calving by caribou. Changing snow cover on the late winter and migratory ranges was the most supported driver of advancing migratory behavior. The ability of caribou to adjust the timing of migratory and reproductive behavior in response to changing environmental conditions demonstrates the potential resilience of the species to some aspects of climate change.

Clinical Accuracy of J-Sign Measurement Compared to Magnetic Resonance Imaging.

BACKGROUND: The J-sign is defined as lateral patellar translation over the anterolateral femur proximal to the trochlear groove during active leg extension. Dynamic magnetic resonance imaging (MRI) techniques allow for quantification of the J-sign using a variety of published indices. However, to date, clinical quantification of the J-sign has not been reliably described. The purpose of the present study is to assess the accuracy of clinically quantifying the J-sign compared with objective MRI data. METHODS: All patients in this case series were indicated for Fulkerson osteotomy due to recurrent lateral patellar instability and examined preoperatively for the presence of J-sign. The J-sign was estimated by placing a finger on the lateral edge of the trochlea and estimating the lateral translation of the patella while the patient actively extended the knee from 30 degrees of flexion to maximum extension. Independent preoperative measurements were obtained by both the senior author and a resident and compared to dynamic MRI measurements read by independent investigators. RESULTS: Preoperative physical examination for the presence of the J-sign was conducted on 10 patients (10 knees). The average difference between clinical and MRI J-sign measurement was 4.32 mm (range 0.2 - 10.4 mm). There was no significant difference between the clinical and MRI J-sign measurements (p = 0.2579). Clinical measurements of the J-sign differed by an average of 2.2 mm between the two examiners (range 0 - 5 mm). CONCLUSIONS: Clinical quantification of the Jsign showed relative imprecision when compared with MRI measurements of the modified lateral patellar edge (LPE), though in several patients we did achieve accurate J-sign assessment. If further research can validate this technique as accurate and consistent using larger patient populations, it could aid in the development of surgical treatment plans for patients presenting with patellar instability, and serve as an objective assessment of alignment in the postoperative period.

Monitoring sulfide-oxidizing biofilm activity on cement surfaces using non-invasive self-referencing microsensors.

Microbially influenced corrosion (MIC) in concrete results in significant cost for infrastructure maintenance. Prior studies have employed molecular techniques to identify microbial community species in corroded concrete, but failed to explore bacterial activity and functionality during deterioration. In this study, biofilms of different sulfur-oxidizing bacteria compositions were developed on the surface of cement paste samples to simulate the natural ecological succession of microbial communities during MIC processes. Noninvasive, self-referencing (SR) microsensors were used to quantify real time changes of oxygen, hydrogen ion and calcium ion flux for the biofilm to provide more information about bacterial behavior during deterioration. Results showed higher transport rates in oxygen consumption, and hydrogen ion at 4 weeks than 2 weeks, indicating increased bacterial activity over time. Samples with five species biofilm had the highest hydrogen ion and calcium ion transport rates, confirming attribution of acidophilic sulfur-oxidizing microorganisms (ASOM). Differences in transport rates between three species samples and two species samples confirmed the diversity between Thiomonas intermedia and Starkeya novella. The limitations of SR sensors in corrosion application could be improved in future studies when combined with molecular techniques to identify the roles of major bacterial species in the deterioration process.

Subpopulation structure of caribou (Rangifer tarandus L.) in arctic and subarctic Canada.

Effective management and conservation of species, subspecies, or ecotypes require an understanding of how populations are structured in space. We used satellite-tracking locations and hierarchical and fuzzy clustering to quantify subpopulations within the behaviorally different barren-ground caribou (Rangifer tarandus groenlandicus), Dolphin and Union island caribou (R. t. groenlandicus x pearyi), and boreal (R. t. caribou) caribou ecotypes in the Northwest Territories and Nunavut, Canada. Using a novel approach, we verified that the previously recognized Cape Bathurst, Bluenose-West, Bluenose-East, Bathurst, Beverly, Qamanirjuaq, and Lorillard barren-ground subpopulations were robust and that the Queen Maude Gulf and Wager Bay barren-ground subpopulations were organized as individuals. Dolphin and Union island and boreal caribou formed one and two distinct subpopulation, respectively, and were organized as individuals. Robust subpopulations were structured by strong annual spatial affiliation among females; subpopulations organized as individuals were structured by migratory connectivity, barriers to movement, and/or habitat discontinuity. One barren-ground subpopulation used two calving grounds, and one calving ground was used by two barren-ground subpopulations, indicating that these caribou cannot be reliably assigned to subpopulations solely by calving-ground use. They should be classified by annual spatial affiliation among females. Annual-range size and path lengths varied significantly among ecotypes, including mountain woodland caribou (R. t. caribou), and reflected behavioral differences. An east-west cline in annual-range sizes and path lengths among migratory barren-ground subpopulations likely reflected differences in subpopulation size and habitat conditions and further supported the subpopulation structure identified.

Adjunctive use of the Rinspiration system for fluidic thrombectomy during primary angioplasty: the Rinspiration international registry.

BACKGROUND: Atherothrombotic embolization during primary percutaneous coronary intervention (PCI) induces microvascular obstruction and reduces myocardial tissue reperfusion. A variety of thrombectomy devices have been evaluated as an adjunct to primary PCI in patients with ST-elevation myocardial infarction (STEMI) to reduce distal embolization. Results have been inconsistent and difficult to predict. The aim of this study was to investigate the safety and efficacy of an innovative thrombectomy device, the Rinspiration System, which simultaneously "rinses" the vessel with turbulent flow and aspirates thrombus. METHODS: We prospectively enrolled 109 patients at six academic institutions in three countries referred for primary or rescue PCI for STEMI presenting within 12 hr of symptom onset. The primary endpoint was >or=50% ST-segment elevation resolution (STR) measured 60 min after PCI by continuous electrocardiographic recording, Secondary end points included STR > 70% at 60 min, final TIMI flow, myocardial blush score, and 30-day major adverse cardiac events (MACE). RESULTS: Mean symptom-to-PCI time was 4.7 +/- 2.7 hr. Rinspiration was successfully delivered in 98% of cases. Final TIMI three flow was achieved in 89% of patients and myocardial blush >or=2 in 78%. Rates of STR >or= 50% and >70% at 60 min were 97 and 80%, respectively. No device-related complications were observed. Thirty-day MACE rate was 4.6%. CONCLUSIONS: This international multicenter registry demonstrates that the adjunctive use of Rinspiration during primary PCI is safe and feasible. The excellent STR data compare favorably with results of previous trials using different devices for thrombus management, indicating a potential clinical benefit.

A proposed nomenclature and diagnostic criteria for protein-energy wasting in acute and chronic kidney disease.

The recent research findings concerning syndromes of muscle wasting, malnutrition, and inflammation in individuals with chronic kidney disease (CKD) or acute kidney injury (AKI) have led to a need for new terminology. To address this need, the International Society of Renal Nutrition and Metabolism (ISRNM) convened an expert panel to review and develop standard terminologies and definitions related to wasting, cachexia, malnutrition, and inflammation in CKD and AKI. The ISRNM expert panel recommends the term 'protein-energy wasting' for loss of body protein mass and fuel reserves. 'Kidney disease wasting' refers to the occurrence of protein-energy wasting in CKD or AKI regardless of the cause. Cachexia is a severe form of protein-energy wasting that occurs infrequently in kidney disease. Protein-energy wasting is diagnosed if three characteristics are present (low serum levels of albumin, transthyretin, or cholesterol), reduced body mass (low or reduced body or fat mass or weight loss with reduced intake of protein and energy), and reduced muscle mass (muscle wasting or sarcopenia, reduced mid-arm muscle circumference). The kidney disease wasting is divided into two main categories of CKD- and AKI-associated protein-energy wasting. Measures of chronic inflammation or other developing tests can be useful clues for the existence of protein-energy wasting but do not define protein-energy wasting. Clinical staging and potential treatment strategies for protein-energy wasting are to be developed in the future.

Drug eluting stents and the critical path initiative: Evolving paradigms for safety evaluation.

Recent discussions between FDA and other stakeholders have focused on the benefits and risks associated with drug eluting stents (DES). A particular topic of focus is DES thrombosis, a rare, but serious, clinical event that may occur months to years after the initial implantation. FDA continues vigilant postmarket surveillance of DES currently on the market and is working with stent manufactures to ensure that new DES platforms in the development pipeline are safe and effective. FDA is also taking steps, under its Critical Path Initiative (CPI) [FDA. Innovation or Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products, March 2004.http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html], to help address current and future DES safety issues. This article describes some of these activities.:

Metabolic and clinical consequences of metabolic acidosis.

Acid-base balance is precisely regulated by pulmonary and renal responses while body buffers help to control pH. When its regulation becomes abnormal, accumulation of hydrogen ions cause metabolic acidosis and several responses are activated. These responses interfere with the metabolism of bones and muscle. Metabolic acidosis induces abnormalities in the release and function of several hormones including defects in growth hormone, IGF-1, insulin, glucocorticoids, thyroid hormone, parathyroid hormone and vitamin D. Clinical consequences of these abnormal metabolic responses include impaired growth of infants and children and loss of bone and muscle mass in adults. Notably, abnormalities in bone and muscle metabolism can be present even when there is little or no decrease in the plasma bicarbonate concentration. The abnormalities can be corrected by treatment with NaHCO 3 . In patients with chronic kidney disease, many abnormalities in bone and muscle metabolism can be directly linked to the presence of metabolic acidosis and these abnormalities can be largely corrected by treating acidosis with NaHCO3. Recent insights indicate that several consequences of metabolic acidosis including the development of insulin resistance can stimulate muscle protein degradation by activating proteolytic mechanisms. To avoid abnormalities in metabolism and the loss of bone and muscle, metabolic acidosis must be corrected in normal adults and in patients with kidney disease.

Regulation of epithelial sodium channels by the ubiquitin-proteasome proteolytic pathway.

Amiloride-sensitive epithelial Na+ channels (ENaC) play a crucial role in Na+ transport and fluid reabsorption in the kidney, lung, and colon. The magnitude of ENaC-mediated Na+ transport in epithelial cells depends on the average open probability of the channels and the number of channels on the apical surface of epithelial cells. The number of channels in the apical membrane, in turn, depends on a balance between the rate of ENaC insertion and the rate of removal from the apical membrane. ENaC is made up of three homologous subunits: alpha, beta, and gamma. The COOH-terminal domain of all three subunits is intracellular and contains a proline-rich motif (PPxY). Mutations or deletion of this PPxY motif in the beta- and gamma-subunits prevent the binding of one isoform of a specific ubiquitin ligase, neural precursor cell-expressed, developmentally downregulated protein (Nedd4-2), to the channel in vitro and in transfected cell systems, thereby impeding ubiquitin conjugation of the channel subunits. Ubiquitin conjugation would seem to imply that ENaC turnover is determined by the ubiquitin-proteasome system, but when Madin-Darby canine kidney cells are transfected with ENaC, ubiquitin conjugation apparently leads to lysosomal degradation. However, in untransfected renal cells (A6) expressing endogenous ENaC, ENaC is indeed degraded by the ubiquitin-proteasome system. Nonetheless, in both transfected and untransfected cells, the rate of ENaC degradation is apparently controlled by Nedd4-2 activity. In this review, we discuss the role of the ubiquitin conjugation and the alternative degradative pathways (lysosomal or proteasomal) in regulating the rate of ENaC turnover in untransfected renal cells and compare this regulation to that of transfected cell systems.

Role of Nedd4-2 and polyubiquitination in epithelial sodium channel degradation in untransfected renal A6 cells expressing endogenous ENaC subunits.

Amiloride-sensitive epithelial sodium channels (ENaC) are responsible for transepithelial Na(+) transport in the kidney, lung, and colon. The channel consists of three subunits (alpha, beta, and gamma). In Madin-Darby canine kidney (MDCK) cells and Xenopus laevis oocytes transfected with all three ENaC subunits, neural precursor cell-expressed developmentally downregulated protein (Nedd4-2) promotes ubiquitin conjugation of ENaC. For native proteins in some cells, ubiquitin conjugation is a signal for their degradation by the ubiquitin-proteasome pathway, whereas in other cell types ubiquitin conjugation is a signal for endocytosis and lysosomal protein degradation. When ENaC are transfected into MDCK cells, ubiquitin conjugation leads to lysosomal degradation. In this paper, we characterize the involvement of the ubiquitin-proteasome proteolytic pathway in the regulation of functional ENaC in untransfected renal A6 cells expressing native ENaC subunits. In contrast to transfected cells, we show that total cellular alpha-, beta-, and gamma-ENaC subunits are polyubiquitinated and that ubiquitin conjugation of subunits increases when the cells are treated with a proteasome inhibitor. We show that Nedd4-2 is associated with alpha- and beta-subunits and is associated with the apical membrane. We also show the Nedd4-2 can regulate the number of functional ENaC subunits in the apical membrane. The results reported here suggest that the ubiquitin-proteasome proteolytic pathway is an important determinant of ENaC function in untransfected renal cells expressing endogenous ENaC.

Molecular mechanisms activating muscle protein degradation in chronic kidney disease and other catabolic conditions.

Muscle atrophy is a prominent feature of chronic kidney disease (CKD) and is frequent in other catabolic conditions. Results from animal models of these conditions as well as patients indicate that atrophy is mainly owing to accelerated muscle proteolysis in the ubiquitin-proteasome (Ub-P'some) proteolytic system. The Ub-P'some system, however, rapidly degrades actin or myosin but cannot breakdown actomyosin or myofibrils. Consequently, another protease must initially cleave the complex structure of muscle. We identified caspase-3 as an initial and potentially rate-limiting proteolytic step that cleaves actomyosin/myofibrils to produce substrates degraded by the Ub-P'some system. In rodent models of CKD and other catabolic conditions, we find that caspase-3 is activated and cleaves actomyosin to actin, myosin and their fragments. This initial proteolytic step in muscle leaves a characteristic footprint, a 14-kDa actin band, providing a potential diagnostic tool to detect muscle catabolism. We also found that stimulation of caspase-3 activity depends on inhibition of IRS-1-associated phosphatidylinositol 3-kinase (PI3K) activity; inhibiting PI3K in muscle cells also leads to expression of a critical E3-ubiquitin-conjugating enzyme involved in muscle protein breakdown: atrogin-1/MAFbx. Thus, protein breakdown by caspase-3 and the ubiquitin-proteasome system in muscle are stimulated by the same signal: a low PI3K activity. These responses could yield therapeutic strategies to block muscle atrophy.

Effects of high doses of glucocorticoids on free amino acids, ribosomes and protein turnover in human muscle.

BACKGROUND: Treatment with glucocorticosteroids causes a negative nitrogen balance, but the kinetic mechanisms responsible for this catabolic effect are controversial. We investigated the effects of 60 mg day(-1) prednisolone on protein synthesis and degradation in human skeletal muscle. MATERIALS AND METHODS: Healthy adults (n = 9) were studied in the postabsorptive state, before and after 3 days of prednisolone treatment. The L-[ring 2,6(-3)H(5)]-phenylalanine tracer technique, concentration and size distribution of the ribosomes, mRNA content of the ubiquitin-proteasome pathway components in muscle, phenylalanine flux across the leg, and the free amino acid concentrations in skeletal muscle were used to study muscle protein metabolism. RESULTS: The concentrations of most amino acids in arterial blood increased after prednisolone. There were also increased effluxes of phenylalanine, asparagine, arginine, alanine, methionine and isoleucine from the leg. The rate of protein degradation, as measured by the appearance rate (Ra) of phenylalanine, increased by 67% (P = 0.023) which, together with a doubling of the net release of phenylalanine from the leg (P = 0.007), indicated accelerated protein degradation. The pathway was not identified but there was no significant increase in mRNAs' encoding components of the ubiquitin-proteasome pathway. There was a 6% reduction in polyribosomes (P = 0.007), suggesting a decrease in the capacity for protein synthesis, although there was no measured decrease in the rate of protein synthesis. CONCLUSIONS: These findings indicate that high doses of prednisolone lead to a sharp increase in net protein catabolism, which depends more on enhanced protein breakdown, and an uncertain effect on protein synthesis. The mechanisms stimulating proteolysis and the pathway stimulated to increase muscle protein degradation should be explored.

Levels of alpha1 acid glycoprotein and ceruloplasmin predict future albumin levels in hemodialysis patients.

BACKGROUND: Serum albumin concentration predicts mortality in hemodialysis (HD) patients. While serum albumin concentration correlates with serum concentration of C-reactive protein (CRP) and is dependent upon CRP in multiple regression models in cross sectional studies, CRP does not predict future albumin levels, possibly because CRP changes rapidly, yielding large month-to-month variability in CRP. If inflammation causes rather than is simply associated with hypoalbuminemia, then changes in the levels of acute phase proteins should precede changes in serum albumin concentration. METHODS: The levels of long-lived positive and negative acute-phase proteins (APPs) (C-reactive protein, ceruloplasmin, alpha1 acid glycoprotein, transferrin and albumin) were measured longitudinally in 64 HD patients and a regression model was constructed to predict future albumin levels. Normalized protein catabolic rate (nPCR) was measured monthly. The number of repeated measurements ranged from 9 to 39 in each patient (median 22 and a mean of 23 measurements). To construct a model that would predict serum albumin concentration at any time j, values of all longitudinally measured APPs, positive and negative at any time j - 1, approximately 30 days prior to time j, were used. Other demographic factors (such as, race, access type, and cause of renal failure) also were incorporated into the model. RESULTS: The model with the best fit for predicting serum albumin at time j included albumin, ceruloplasmin, and alpha1 acid glycoprotein measured at time j - 1. The only demographic variable with subsequent predictive value was diabetes. CONCLUSIONS: The finding that changes in the concentration of the long lived APPs measured one month earlier are associated with predictable changes in the future concentration of serum albumin suggest that changes in inflammation are likely to be causal in determining serum albumin concentration in hemodialysis patients.

Mechanisms activated by kidney disease and the loss of muscle mass.

The daily turnover of cellular proteins is large, with amounts equivalent to the protein contained in 1.0 to 1.5 kg of muscle. Consequently, even a small, persistent increase in the rate of protein degradation or decrease in protein synthesis will result in substantial loss of muscle mass. Activation of protein degradation in the ubiquitin-proteasome system is the mechanism contributing to loss of muscle mass in kidney disease. Because other catabolic conditions also stimulate this system to cause loss of muscle mass, the identification of activating signals is of interest. A complication of kidney disease, metabolic acidosis, activates this system in muscle by a process that requires glucocorticoids. The influence of inflammatory cytokines on this system in muscle is more complicated, as evidence indicates that cytokines suppress the system, but glucocorticoids block the effect of cytokines to slow protein breakdown in the system. New information identifying mechanisms that activate protein breakdown and the rebuilding of muscle fibers would lead to therapies that successfully prevent the loss of muscle mass in kidney disease and other catabolic illnesses.

[Effect of losartan on renal and cardiovascular complications of patients with type 2 diabetes and nephropathy]. / Effekt af losartan på nyre- og kardiovaskulaere komplikationer hos patienter med type 2-diabetes og nefropati.

INTRODUCTION: Diabetic nephropathy is the leading cause of end-stage renal disease. Interruption of the renin-angiotensin system slows the progression of renal disease in type 1 diabetic patients, but similar data are not available for type 2, the most common form of diabetes. We assessed the role of the angiotensin II receptor antagonist, losartan, in type 2 diabetic patients with nephropathy. MATERIAL AND METHODS: One thousand five hundred and thirteen patients were enrolled in this randomised, placebo-controlled study of losartan (50 to 100 mg, once daily) or placebo, in addition to conventional antihypertensive treatment (calcium antagonists, diuretics, alpha- and beta-blockers, centrally acting agents) for a mean of 3.4 years. The primary outcome was the composite of doubling of baseline serum creatinine, end-stage renal disease, or death. Secondary end points included a composite of cardiovascular morbidity and mortality, proteinuria, and the progression rate of renal disease. RESULTS: Baseline demographics in the two groups were similar. Three hundred and twenty-seven patients receiving losartan reached the primary end point, as compared with 359 on placebo (risk reduction = 16 per cent, p = 0.02). Losartan reduced the incidence of doubling of serum creatinine (risk reduction = 25 per cent, p = 0.006) and end-stage renal disease (risk reduction = 28 per cent, p = 0.002), but had no effect on death. Benefits exceeded that attributable to changes in blood pressure. The composite of cardiovascular morbidity and mortality was similar in the two groups, except hospitalisation for heart failure, which was reduced with losartan (risk reduction = 32 per cent, p = 0.005). Proteinuria declined by 35 per cent with losartan (p < 0.001). DISCUSSION: Losartan conferred significant renal benefits in type 2 diabetic patients with nephropathy and was generally well tolerated.

Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy.

BACKGROUND: Diabetic nephropathy is the leading cause of end-stage renal disease. Interruption of the renin-angiotensin system slows the progression of renal disease in patients with type 1 diabetes, but similar data are not available for patients with type 2, the most common form of diabetes. We assessed the role of the angiotensin-II-receptor antagonist losartan in patients with type 2 diabetes and nephropathy. METHODS: A total of 1513 patients were enrolled in this randomized, double-blind study comparing losartan (50 to 100 mg once daily) with placebo, both taken in addition to conventional antihypertensive treatment (calcium-channel antagonists, diuretics, alpha-blockers, beta-blockers, and centrally acting agents), for a mean of 3.4 years. The primary outcome was the composite of a doubling of the base-line serum creatinine concentration, end-stage renal disease, or death. Secondary end points included a composite of morbidity and mortality from cardiovascular causes, proteinuria, and the rate of progression of renal disease. RESULTS: A total of 327 patients in the losartan group reached the primary end point, as compared with 359 in the placebo group (risk reduction, 16 percent; P=0.02). Losartan reduced the incidence of a doubling of the serum creatinine concentration (risk reduction, 25 percent; P=0.006) and end-stage renal disease (risk reduction, 28 percent; P=0.002) but had no effect on the rate of death. The benefit exceeded that attributable to changes in blood pressure. The composite of morbidity and mortality from cardiovascular causes was similar in the two groups, although the rate of first hospitalization for heart failure was significantly lower with losartan (risk reduction, 32 percent; P=0.005). The level of proteinuria declined by 35 percent with losartan (P<0.001 for the comparison with placebo). CONCLUSIONS: Losartan conferred significant renal benefits in patients with type 2 diabetes and nephropathy, and it was generally well tolerated.

Angiotensin II induces skeletal muscle wasting through enhanced protein degradation and down-regulates autocrine insulin-like growth factor I.

We previously showed that angiotensin II (ang II) infusion in the rat produces cachexia and decreases circulating insulin-like growth factor I (IGF-I). The weight loss derives from an anorexigenic response and a catabolic effect of ang II. In these experiments we assessed potential catabolic mechanisms and the involvement of the IGF-I system in these responses to ang II. Ang II infusion caused a significant decrease in body weight compared with that of pair-fed control rats. Kidney and left ventricular weights were significantly increased by ang II, whereas fat tissue was unchanged. Skeletal muscle mass was significantly decreased in the ang II-infused rats, and a reduction in lean muscle mass was a major reason for their overall loss of body weight. In skeletal muscles, ang II did not significantly decrease protein synthesis, but overall protein breakdown was accelerated; inhibiting lysosomal and calcium-activated proteases did not reduce the ang II-induced increase in muscle proteolysis. Circulating IGF-I levels were 33% lower in ang II rats vs. control rats, and this difference was reflected in lower IGF-I messenger RNA levels in the liver. Moreover, IGF-I, IGF-binding protein-3, and IGF-binding protein-5 messenger RNAs in the gastrocnemius were significantly reduced. To investigate whether the reduced circulating IGF-I accounts for the loss in muscle mass, we increased circulating IGF-I by coinfusing ang II and IGF-I, but this did not prevent muscle loss. Our data suggest that ang II causes a loss in skeletal muscle mass by enhancing protein degradation probably via its inhibitory effect on the autocrine IGF-I system.