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Biomedical subjects

V E Baracos

Publications and source records attributed to V E Baracos.

At least 19 recordsLinked to original sources
PubMed2001

Management of muscle wasting in cancer-associated cachexia: understanding gained from experimental studies.

BACKGROUND: Cancer-associated cachexia is a syndrome of progressive wasting of body energy (adipose) and protein (skeletal muscle) reserves. Cachexia occurs in a majority of advanced cancer patients. Extensive loss of muscle mass is one factor likely to be associated with fatigue in cancer patients. METHODS: Research with animal models of cancer-associated cachexia that have focused on the processes of muscle protein synthesis and degradation are reviewed in this article. Modulation of the production or action of anabolic and catabolic factors known to regulate muscle protein synthesis and degradation have been employed to identify causal factors in muscle wasting. RESULTS: Impaired muscle protein synthesis and activation of catabolism participate in cancer-associated muscle atrophy. The relative roles of multiple factors, including a low level of physical activity, poor nutritional status, and secretion of catabolic mediators of host or tumor origin, are discussed herein. A diversity of putative mediators has been identified, and a number of common themes are beginning to emerge. CONCLUSIONS: Multiple distinct catabolic profiles exist in animal models of cancer-associated muscle wasting. The presence of these catabolic phenotypes in cancer patients must be determined, and the application of successful treatments will depend on our ability to determine which categories of patients experience the greatest benefit.

Animals↗
PubMed2001

Nutrition and athletic performance.

This supplement is based on presentations made at the "First International Congress on Nutrition and Athletic Performance" held at the Shaw Conference Centre, Edmonton, Alberta, Canada, August 8-11, 2001. This conference was stimulated by an increasing awareness of the potential benefits and risks of diet modification and supplementation for elite athletic performance. This supplement summarizes recent findings and commentary on new research directions in nutrition and athletic performance by 22 invited plenary speakers from around the world.

Humans↗
PubMed2001

Coordinate expression of matrix-degrading proteinases and their activators and inhibitors in bovine skeletal muscle.

Matrix metalloproteinases (MMP) responsible for degradation of connective tissue are found in most tissues. The MMP are regulated at the levels of transcription, zymogen activation by plasmin or membrane-type- (MT) MMP, and control of enzyme activity by tissue inhibitors of metalloproteinases (TIMP). Whole bovine skeletal muscle showed multiple MMP activities on gelatin zymography and also expressed mRNA encoding MMP-1, -2, -9, -14, and -16, tissue inhibitors of metalloproteinase (TIMP)-1, -2, and -3 and plasminogen activator and its receptor. Purified intramuscular fibroblasts and myogenic cell culture derived from satellite cells expressed most or all of these elements. Statistical analysis (n = 35) revealed a strong positive correlation among the mRNA levels of several elements of the MMP system, including MMP-2, MMP-14, TIMP-1, -2, and -3 (r = 0.614 to 0.930, P < 0.0001). Our results provide an extensive profile of an extracellular proteolytic cascade involving MMP in skeletal muscle and suggest that 1) the activation cascades of muscle MMP may be initiated by both plasmin and membrane-type MMP; 2) a group of genes involved in the same "arm" of zymogen activation are coexpressed in this tissue; and 3) skeletal muscle cells, in addition to the intramuscular fibroblasts, express an extensive complement of MMP and related proteins.

Animals↗
PubMed2000

Regulation of skeletal-muscle-protein turnover in cancer-associated cachexia.

Cancer is frequently associated with anorexia, weight loss, negative nitrogen balance, and skeletal-muscle wasting. Depletion of skeletal-muscle mass is critical to overall survival of the patient, can prolong rehabilitation to normal function after recovery, and decreases quality of life in a palliative-care setting. The biochemical and physiologic bases of cancer-associated muscle wasting have been most fully investigated in animal models. These studies provide evidence for suppressed protein synthesis and activated proteolysis in cancer-associated muscle wasting and indicate a need for both anabolic and anticatabolic therapies. Several humoral factors of host or tumor origin are implicated in altered muscle-protein metabolism, including cytokines, metabolites of arachidonic acid, and a proteolysis-inducing glycoprotein; their interrelationships are less well characterized. Several catabolic mediators may share common downstream mechanisms because they ultimately activate the ATP-, ubiquitin-, and proteasome-dependent intracellular proteolytic system. Although important gaps in our current understanding remain, data available from animal studies can be used as a basis to develop relevant studies in human subjects.

Animals↗
PubMed2000

Anabolic and catabolic mediators of intestinal protein turnover: a new experimental approach.

Studies on regulation of protein turnover in skeletal muscle have revealed the important contributions of protein synthesis and catabolism to tissue protein balance, and have identified a host of specific anabolic and catabolic stimuli and biochemical mechanisms that regulate these processes. This knowledge is critical to current efforts designed to promote anabolism and limit atrophy. Of the tissues with a potentially large contribution to whole-body amino acid metabolism, protein turnover of the intestine stands out as being poorly understood. The intestine is subject to complexities in regulation of its metabolism that are not apparent for other tissues. The study of intestinal protein turnover also entails some important technical challenges. We recently developed an in-situ experimental system for study of intestinal mucosal protein synthesis with the following unique features: multiple observations within an animal; controlled delivery of nutritional stimuli to the apical side, basolateral side, or both; and luminal delivery of tracer in a flooding dose for determination of protein synthesis. We have begun to use the system to test the specific roles of individual luminal nutrients in regulation of mucosal protein synthesis. We have also used protease gene expression as an index of potential regulation of catabolic pathways.

Animals↗
PubMed2000

Cytokines and endotoxin induce cytokine receptors in skeletal muscle.

Proinflammatory cytokines are important factors in the regulation of diverse aspects of skeletal muscle function; however, the muscle cytokine receptors mediating these functions are uncharacterized. Binding kinetics (dissociation constant = 39+/-4.7 x 10(-9) M, maximal binding = 3.5+/-0.23 x 10(-12) mol/mg membrane protein) of muscle tumor necrosis factor (TNF) receptors were obtained. Skeletal muscle was found to express mRNAs encoding interleukin-1 type I and II receptors, interleukin-6 receptor (IL-6R), and interferon-gamma receptor by RT-PCR, but these receptors were below limits of detection of ligand-binding assay (> or =1 fmol binding sites/mg protein). Twenty-four hours after intraperitoneal administration of endotoxin to rats, TNF receptor type II (TNFRII) and IL-6R mRNA were increased in skeletal muscle (P<0.05). In cultured L6 cells, the expression of mRNA encoding TNFRII and IL-6R receptors was induced by TNF-alpha, and all six cytokine receptor mRNA were induced by a mixture of TNF-alpha, IFN-gamma, and endotoxin (P<0.05). This suggests that the low level of cytokine receptor expression is complemented by a capacity for receptor induction, providing a clear mechanism for amplification of cytokine responses at the muscle level.

Animals↗
PubMed2000

The activity of transcription factor Stat5 responds to prolactin, growth hormone, and IGF-I in rat and bovine mammary explant culture.

Signal transducer and activator of transcription-5 (Stat5) is known to play a critical role in prolactin-induced beta-casein gene transcription in rodents. In nonmammary cells, Stat5 is activated by multiple hormones and cytokines, including growth hormone. We hypothesized that Stat5 may serve as a common point in the signal transduction pathways of hormones that promote milk protein gene expression in bovine mammary cells, which are regulated by GH and IGF-I in addition to prolactin. Assays for Stat5 DNA binding activity and protein were validated in mammary explant culture. The Stat5 protein abundance was not changed by any of the short-term hormonal treatments used in our study, suggesting that short-term regulation of Stat5 is predominantly at the level of protein activation. Both rat and bovine explant culture showed a rapid stimulation of Stat5 DNA binding activity by prolactin, GH, and IGF-I at the high concentrations typically used in explant cultures as well as at levels within physiologic ranges. Growth hormone stimulated Stat5 activity at a lower concentration in bovine than in rat cultures, but in both species the presence of GH increased the response of Stat5 activity to prolactin. These results suggest that transcription factor Stat5 may represent part of a common route by which different extracellular signals converge and are transduced intracellularly to coordinately regulate cell function in the mammary gland.

Animals↗
PubMed2000

Physiological levels of Stat5 DNA binding activity and protein in bovine mammary gland.

Signal transducer and activator of transcription (Stat)5 has been implicated in the signal transduction pathways of several factors that are lactogenic or galactopoeitic in mammary cells, including prolactin, GH, and IGF-I. Data from cell or explant culture support the concept that Stat5 may represent part of a common route by which different extracellular signals converge and are transduced into the cell. There are few data on Stat5 activity and level in vivo, and we set out to determine whether physiological stimuli of milk synthesis, including GH, GH-releasing factor, and milking frequency, would be associated with alterations in Stat5 activity or protein. We measured Stat5 DNA binding activity using electrophoretic mobility shift assay and Stat5 protein by Western blot in bovine mammary tissue obtained by biopsy or slaughter. Stat5 activity was absent in nonlactating, nonpregnant cows and was present in late pregnancy and throughout lactation. Stat5 activity varied considerably among cows at similar stages of lactation. Mammary Stat5 activity and protein were determined in hormone-treated lactating cows and mammary quarters of cows milked at different frequencies. Infusion of GH and GH-releasing factor for 2 mo significantly raised levels of milk production and depressed mammary Stat5 activity without influencing Stat5 protein abundance. Mammary Stat5 was also influenced by milking frequency; once-daily milking reduced milk production, Stat5 activity, and protein abundance compared with twice-daily milking. Analysis of mammary Stat5 in relation to milk protein concentration in pooled data from lactating cows indicated that Stat5 activity was correlated (r = 0.505, P < 0.05) with average milk protein concentration and not related to milk protein yield (P > 0.05). These results show that both Stat5 protein and Stat5 activity are modulated by different physiological signals in vivo and suggest that Stat5 lies within in the zone where signal transduction cascades from a variety of factors are convergent. Further work is required to clarify the role of Stat5 in relation to other factors in regulation of milk protein gene expression.

Animals↗
PubMed1999

Luminal amino acids acutely decrease intestinal mucosal protein synthesis and protease mRNA in piglets.

Because parenteral feeding is associated with negative N balance and reduced rates of protein synthesis in intestinal mucosa, we hypothesized that luminal exposure to specific amino acids or energy fuels would stimulate intestinal protein synthesis. We studied the acute effects of luminal nutrients on mucosal protein synthesis in the absence of systemic influences. Multiple jejunal segments constructed in piglets deprived of food overnight (n = 6) were randomly assigned to luminal perfusion with saline, 30 mmol/L amino acid mixture with or without 50 mmol/L glucose, or 30 mmol/L glutamine for 90 min. Protein synthesis was then measured by luminal perfusion with L-[2,6-(3)H]-phenylalanine. Energy substrates (glucose, short-chain fatty acids or beta-hydroxybutyrate) had no effect on mucosal protein synthesis. Relative to saline, a 30 mmol/L amino acid mixture or 30 mmol/L glutamine suppressed mucosal protein synthesis by 20-25% (P < 0.05). On the basis of these surprising results, we speculated that a coordinate reduction of proteolytic processes would be required to maintain positive intestinal N balance. Although intestinal protein catabolism cannot be assessed directly, the 30 mmol/L amino acid mixture acutely suppressed mucosal levels of mRNA encoding ubiquitin, 14-kDa ubiquitin conjugating enzyme and the C9 subunit of the proteasome by 20-30% (P < 0.05), demonstrating the sensitivity of components of the ATP-ubiquitin proteolytic pathway to acute regulation by nutrients. The suppression of protein synthesis by luminal amino acids in the absorptive state might lower intestinal utilization of amino acids to ensure efficient allocation of absorbed nutrients to nonintestinal tissues.

Amino Acids↗
PubMed1999

Jejunal mucosal protein synthesis: validation of luminal flooding dose method and effect of luminal osmolarity.

To validate a system to study acute regulation of protein synthesis in intestinal mucosa by luminal nutrients, we compared the fractional rate of protein synthesis (Ks) in jejunal mucosa using the intravenous flooding dose technique with the administration of a comparable concentration and specific activity of tracer in a luminal perfusate. Routes of tracer administration and surgery and perfusion trauma had no effect on mucosal Ks. Furthermore, four 10-cm jejunal segments (within a piglet) simultaneously but separately perfused with a luminal flooding dose had similar Ks values (mean, 43 +/- 2%/day; P > 0.05). Nutrient solutions perfused through four intestinal segments within an animal did not affect plasma levels of most amino acids or glucose. Because cellular hydration is important in regulating metabolism, the effects of physiological variation in luminal osmolarity were studied. Luminal osmolarities between 250 and 380 mosM did not affect mucosal Ks. The system described allows multiple comparisons within an animal and provides a robust model to study acute modulation of protein synthesis in intestinal mucosa by luminal stimuli.

Amino Acids↗
PubMed1999

Amino acid nutrition and immune function in tumour-bearing rats: a comparison of glutamine-, arginine- and ornithine 2-oxoglutarate-supplemented diets.

Dietary supplementation with glutamine (Gln), arginine (Arg) or ornithine 2-oxoglutarate (alpha-ketoglutarate; OKG) has attracted recent attention for the potential to improve anti-cancer immune function. However, since these compounds have not been compared systematically in an internally controlled study, their relative efficacy is difficult to estimate. Buffalo rats were fed on nutritionally complete semi-purified diets supplemented with Gln, Arg or OKG for 14 days after implantation of the Morris hepatoma 7777 (n>/=7 per diet). The control diet was made isonitrogenous and isoenergetic by addition of a mixture of non-essential amino acids. After 14 days, peritoneal macrophages and splenocytes were isolated to determine cell phenotypes, macrophage cytostatic activity and natural killer (NK) cell cytotoxicity, as well as nitric oxide (NO) and cytokine production. Diet had no effect on tumour weight (1.6+/-0.2 g; n=59). However, rats fed OKG had increased macrophage cytostatic activity and NK cell cytotoxicity (P<0.05). Although enhanced killing ability by NK cells was associated with higher splenocyte NO production (P<0.04), increased cytotoxicity was not inhibited by a specific inhibitor of inducible NO synthase. The proportion of interleukin-2-receptor-positive T cells after stimulation increased in rats fed OKG (P<0.05); however, cytokine production was not affected by diet. None of OKG, Gln or Arg altered tumour growth compared with a control mixture of non-essential amino acids. These results suggest no net advantage for anti-cancer immunity, but do not preclude benefits in immune responses to disease recurrence or metastasis, therapy or secondary infection.

Analysis of Variance↗
PubMed1998

Anabolic and catabolic mediators.

Negative N balance, and skeletal muscle wasting are associated with many disease states. Depletion of skeletal muscle mass is recognized as critical to overall survival of the patient and can prolong rehabilitation to normal physiological function following recovery. The biochemical mechanisms of muscle wasting have been most fully investigated in animal models. These studies indicate a role for suppressed protein synthesis as well as activated proteolysis, and therefore to a need for both anabolic as well as anti-catabolic therapies. Multiple humoral factors are implicated in altered muscle protein metabolism, however the identity of all of the factors involved and their interrelationships are less well characterized. The role of specific mediators in different clinical instances of muscle protein loss is relatively poorly understood, and successful treatment will depend on the ability to identify the different catabolic phenotypes in patients.

Animals↗
PubMed1998

Feeding lactating primiparous sows to establish three divergent metabolic states: II. Effect on nitrogen partitioning and skeletal muscle composition.

We established an experimental model to study nitrogen (N) partitioning in lactating primiparous sows alimented to three levels of nutrient intake. Thirty-six sows fitted with a gastric cannula and fed a 15.4 MJ DE/kg and 18.6% CP diet were allocated to one of three treatments after farrowing: 1) ad libitum-fed; 2) restricted-fed to 55% of the ad libitum feed intake; and 3) superalimented to at least 125% of the ad libitum feed intake. These feed intakes were successfully achieved throughout lactation. Nitrogen balance was studied for three 5-d periods starting on d 2, 11, and 19 of lactation, and a triceps muscle biopsy was taken on d 26. For all treatments, N intake increased, milk N production increased, urinary N losses decreased, but fecal N losses increased as the 28-d lactation progressed. Restricted-fed sows had the lowest fecal N and urinary losses and mobilized the most maternal protein (-23.0 vs -7.4 +/- 6.5 g N/d for ad libitum-fed sows) during lactation. As a consequence of these economies, and extensive protein mobilization, restricted-fed sows were able to maintain milk N production similar to that of sows on the other treatments. Superalimented sows did not mobilize protein, had the poorest protein digestibility, directed the least digestible N toward milk (40.1 vs 78.3% in restricted-fed sows), and produced amounts of milk N similar to those produced by sows on the other treatments. The treatment differences in N retention measured by N balance were reflected in differences in skeletal muscle variables and urinary creatinine. Skeletal muscle cell size (protein:DNA ratio) and protein synthetic capacity (RNA:DNA ratio) increased in response to feed intake. The protein:DNA ratio increased (P < .01) linearly and the RNA:DNA ratio increased (P < .05) in a curvilinear manner. These data suggest that primiparous sows partition additional retained N toward their maternal reserves rather than milk N. They also suggest that sows fed inadequate N intakes maintain milk production by mobilizing maternal protein reserves. Such sows also conserve maternal N during lactation, possibly by reducing muscle protein synthesis.

Amino Acids↗
PubMed1997

Dietary L-glutamine supplementation reduces the growth of the Morris Hepatoma 7777 in exercise-trained and sedentary rats.

Dietary glutamine supplementation and exercise have been reported independently to enhance immune function and reduce tumor growth. We study the effect of both of these interventions on the growth of the Morris Hepatoma 7777, implanted in 59 female Sprague-Dawley Buffalo rats. Rats were fed a nutritionally complete, purified diet with or without L-glutamine 20 g/kg diet and randomized to swim 3 h/d or to remain sedentary. After 14 d, the mean tumor weight of glutamine-supplemented rats was lower (P < 0.0001) than that of unsupplemented rats (5.8 +/- 0.4 vs. 8.7 +/- 0.5 g, respectively). Exercise did not alter tumor growth. Glutamine supplementation increased [3H] thymidine incorporation by splenocytes incubated with Concanavalin A and the proportion of natural killer cells in spleen, but not cytotoxic activity against YAC-1 cells. Glutamine supplementation did not alter glutamine concentrations in plasma (691 +/- 12 mumol/L) or soleus muscle (5328 +/- 102 pmol/mg) but resulted in higher (P < 0.004) plasma concentrations of leucine, isoleucine and valine, precursors of glutamine. Splenocytes from exercised rats had a higher (P < 0.001) mitogen response than those from sedentary rats. Isolated tumor cells demonstrated high rates of non-oxidative glucose and glutamine metabolism and consumption of glutamine, tryptophan and methionine. However, neither diet nor exercise significantly affected glucose or glutamine metabolism by tumor cells. The precise mechanism of tumor growth suppression by oral glutamine supplementation is not clear but may be related to changes in substrate availability, improved tumor-directed natural killer cytotoxic activity or a faster response to an immune challenge.

Amino Acids↗