Biomedical subjects

D Attaix

Publications and source records attributed to D Attaix.

At least 19 recordsLinked to original sources

PubMed2000

Protein metabolism in the small intestine during cancer cachexia and chemotherapy in mice.

The impact of cancer cachexia and chemotherapy on small intestinal protein metabolism and its subsequent recovery was investigated. Cancer cachexia was induced in mice with colon 26 adenocarcinoma, which is a small and slow-growing tumor characteristic of the human condition, and can be cured with 100% efficacy using an experimental nitrosourea, cystemustine (C6H12ClN3O4S). Both healthy mice and tumor-bearing mice were given a single i.p. injection of cystemustine (20 mg/kg) 3 days after the onset of cachexia. Cancer cachexia led to a reduced in vivo rate of protein synthesis in the small intestine relative to healthy mice (-13 to -34%; P < 0.05), resulting in a 25% loss of protein mass (P < 0.05), and decreased villus width and crypt depth (P < 0.05). In treated mice, acute cytotoxicity of chemotherapy did not promote further wasting of small intestinal protein mass, nor did it result in further damage to intestinal morphology. In contrast, mucosal damage and a 17% reduction in small intestinal protein mass (P < 0.05) were evident in healthy mice treated with cystemustine, suggesting that the effects of chemotherapy on the small intestine in a state of cancer cachexia are not additive, which was an unexpected finding. Complete and rapid recovery of small intestinal protein mass in cured mice resulted from an increase in the rate of protein synthesis compared with healthy mice (23-34%; P < 0.05). Northern hybridizations of mRNA encoding components of the major proteolytic systems suggested that proteolysis may not have mediated intestinal wasting or recovery. A major clinical goal should be to design methods to improve small intestinal protein metabolism before the initiation of chemotherapy.

Adenocarcinoma↗

PubMed1999

Manipulation of the ubiquitin-proteasome pathway in cachexia: pentoxifylline suppresses the activation of 20S and 26S proteasomes in muscles from tumor-bearing rats.

The development of pharmacological approaches for preventing the loss of muscle proteins would be extremely valuable for cachectic patients. For example, severe wasting in cancer patients correlates with a reduced efficacy of chemotherapy and radiotherapy. Pentoxifylline (PTX) is a very inexpensive xanthine derivative, which is widely used in humans as a haemorheological agent, and inhibits tumor necrosis factor transcription. We have shown here that a daily administration of PTX prevents muscle atrophy and suppresses increased protein breakdown in Yoshida sarcoma-bearing rats by inhibiting the activation of a nonlysosomal, Ca(2+)-independent proteolytic pathway. PTX blocked the ubiquitin pathway, apparently by suppressing the enhanced expression of ubiquitin, the 14-kDa ubiquitin conjugating enzyme E2, and the C2 20S proteasome subunit in muscle from cancer rats. The 19S complex and 11S regulator associate with the 20S proteasome and regulate its peptidase activities. The mRNA levels for the ATPase subunit MSS1 of the 19S complex increased in cancer cachexia, in contrast with mRNAs of other regulatory subunits. This adaptation was suppressed by PTX, suggesting that the drug inhibited the activation of the 26S proteasome. This is the first demonstration of a pharmacological manipulation of the ubiquitin-proteasome pathway in cachexia with a drug which is well tolerated in humans. Overall, the data suggest that PTX can prevent muscle wasting in situations where tumor necrosis factor production rises, including cancer, sepsis, AIDS and trauma.

Adenosine Triphosphatases↗

PubMed1999

Adaptation of the ubiquitin-proteasome proteolytic pathway in cancer cachexia.

The ubiquitin-proteasome proteolytic pathway is of major importance in the breakdown of skeletal muscle proteins. The first step in this pathway is the covalent attachment of polyubiquitin chains to the targeted protein. Polyubiquitinylated proteins are then recognized and degraded by the 26S proteasome complex. In this review, we critically analyze recent findings in the regulation of ubiquitinylation of protein substrates and of their subsequent proteasome-dependent degradation in animal models of cancer cachexia. In particular, we discuss the influence of various mediators (anorexia, hormones, prostaglandins, cytokines, and proteolysis-inducing factor) in signaling the activation of ubiquitin-proteasome proteolysis in skeletal muscle. These findings have lead to new concepts that are starting to be used for preventing cachexia in cancer and other wasting diseases.

Animals↗

PubMed1999

Lower recovery of muscle protein lost during starvation in old rats despite a stimulation of protein synthesis.

Sarcopenia could result from the inability of an older individual to recover muscle lost during catabolic periods. To test this hypothesis, we compared the capacity of 5-day-refed 12- and 24-mo-old rats to recover muscle mass lost after 10 days without food. We measured gastrocnemius and liver protein synthesis with the flooding-dose method and also measured nitrogen balance, 3-methylhistidine excretion, and the gene expression of components of proteolytic pathways in muscle comparing fed, starved, and refed rats at each age. We show that 24-mo-old rats had an altered capacity to recover muscle proteins. Muscle protein synthesis, inhibited during starvation, returned to control values during refeeding in both age groups. The lower recovery in 24-mo-old rats was related to a lack of inhibition of muscle proteolysis during refeeding. The level of gene expression of components of the proteolytic pathways did not account for the variations in muscle proteolysis at both ages. In conclusion, this study highlights the role of muscle proteolysis in the lower recovery of muscle protein mass lost during catabolic periods.

Aging↗

PubMed1999

Effects of underfeeding and refeeding on weight and cellularity of splanchnic organs in ewes.

We assessed the effects of a long and severe period of underfeeding, followed by a rapid refeeding with a high-concentrate diet, on weight, protein mass, and cellularity of the splanchnic organs in adult ewes. Twenty-four ewes, allocated to four groups of six, were fed a forage diet (50% regrowth of natural grassland hay and 50% wheat straw) either at maintenance (groups M and MO) or at 40% maintenance (groups U and UO) for 78 d. Groups M and U were then slaughtered, and groups MO and UO were subsequently overfed a high-concentrate diet (52% hay, 20% barley, 16% rapeseed meal, 4% fish meal, and 8% Megalac) at 236% maintenance for 26 d before being slaughtered. During the experiment, feed was adjusted to maintain feed supply at a constant percentage of animal requirements. After slaughter, fresh weight, dry weight, and protein mass of the reticulorumen, omasum, abomasum, small intestine, large intestine, and liver were measured. Cellularity was assessed from nucleic acids and protein contents for both ruminal mucosa and muscular-serosa layers, jejunum, and liver. The concentrations of ubiquitin and cathepsin D mRNA were measured in ruminal mucosa and muscular-serosa layers and in jejunum. Underfeeding decreased protein mass of splanchnic organs, especially in liver (-29%) and reticulorumen (-39%). Refeeding previously underfed animals increased protein mass of liver (+102%) and small intestine (+59%). No carry-over effect of the previous level of intake (UO vs. MO) was observed on the protein mass of splanchnic tissues after 26 d of refeeding. Variations in liver mass were mainly due to hypertrophy, as determined by the protein:DNA ratio, whereas variations in small intestinal mass were mainly due to hyperplasia, as determined by the amount of DNA. By contrast, changes in rumen mass associated with increasing ME intake seemed to be related to hypertrophy in the muscular-serosal component and hyperplasia in the epithelial component. The concentrations of ubiquitin and cathepsin D mRNA in the rumen and jejunum were not modified by feeding level, demonstrating that the expression of these genes for proteolytic enzymes was unchanged under these conditions.

Animal Feed↗

PubMed1998

Effects of alimentary whole proteins versus their small peptide hydrolysates on liver and skeletal muscle during the acute inflammation phase in the rat.

Acute inflammation induces changes in liver proteins with an increase in synthesis of positive acute-phase proteins such as alpha1-acid glycoprotein (alpha1-AGP) and a decrease in synthesis of negative acute-phase proteins such as albumin. This is associated with muscle wasting, mediated by increased proteolysis and impaired protein synthesis. As protein metabolism can be altered in other situations (malnutrition, growth) by the form of the dietary nitrogen, we studied the effects of the molecular form of nitrogen on liver and skeletal muscle adaptation, looking at gene expression for two acute-phase proteins (albumin and alpha1-AGP) and a number of muscle proteins (alpha1-actin, ubiquitin and C9 proteasome subunit). Two groups of 24 Wistar rats (250 g) were injected S/C with 0.125 ml turpentine/rat and were fed one of two liquid diets. These diets had caloric, nitrogen, carbohydrate and lipid content but differed in the molecular form of the nitrogen source (whole protein [WP] versus peptide hydrolysate [PH]). Liver and muscle adaptation were studied at 18, 42 or 66 h after turpentine injection. Weight, deoxyribonucleic acid and protein content of the liver were significantly higher with the WP diet than with the PH diet at 42 h and 66 h. There was more alpha1-AGP messenger ribonucleic acid (mRNA) at 18 h and less albumin mRNA at 42 h. Thus, the PH diet causes a more rapid increase in alpha1-AGP mRNA content and a smaller decrease in albumin mRNA content after turpentine injection than the WP diet. However, the changes in plasma acute-phase proteins (albumin and alpha1-AGP) were similar with the two diets. In skeletal muscle, there was no change in mRNA levels for the C9 proteasome subunit at any time point with both diets compared to the controls. However, there were greater ubiquitin mRNA levels at 18|h and less alpha-actin mRNA levels at 18 h, 42 h and 66 h following turpentine injection in the two dietary groups than in the controls. These results suggest that the molecular form of nitrogen ingested regulates hepatic gene transcription or mRNA stability of acute-phase proteins, during the early period of inflammation, but did not affect the expression of muscle proteins, which was altered by turpentine injection. Post-transcriptional control of acute-phase protein genes may contribute to the maintenance of similar plasma levels.

Actins↗

PubMed1997

Expression of subunits of the 19S complex and of the PA28 activator in rat skeletal muscle.

A precise knowledge of the role of subunits of the 19S complex and the PA28 regulator, which associate with the 20S proteasome and regulate its peptidase activities, may contribute to design new therapeutic approaches for preventing muscle wasting in human diseases. The proteasome is mainly responsible for the muscle wasting of tumor-bearing and unweighted rats. The expression of some ATPase (MSS1, P45) and non ATPase (P112-L, P31) subunits of the 19S complex, and of the two subunits of the PA28 regulator, was studied in such atrophying muscles. The mRNA levels for all studied subunits increased in unweighted rats, and analysis of MSS1 mRNA distribution profile in polyribosomes showed that this subunit entered active translation. By contrast, only the mRNA levels for MSS1 increased in the muscles from cancer rats. Thus, gene expression of the proteasome regulatory subunits depends on a given catabolic state. Torbafylline, a xanthine derivative which inhibits tumor necrosis factor production, prevented the activation of protein breakdown and the increased expression of 20S proteasome subunits in cancer rats, without reducing the elevated MSS1 mRNA levels. Thus, the increased expression of MSS1 is regulated independently of 20S proteasome subunits, and did not result in accelerated proteolysis.

Animals↗

PubMed1997

Glucocorticoids do not regulate the expression of proteolytic genes in skeletal muscle from Cushing's syndrome patients.

Glucocorticoids signal enhanced proteolysis in various instances of muscle atrophy and increased gene expression of components of the lysosomal, Ca(2+)-dependent, and/or ubiquitin-proteasome proteolytic pathways in both rat skeletal muscle and myotubes. Cushing's syndrome is characterized by chronic excessive glucocorticoid production, which results in muscle wasting. We report here no change in messenger RNA levels for cathepsin D (a lysosomal proteinase), m-calpain (a Ca(2+)-activated proteinase), ubiquitin, 14-kDa ubiquitin-activating enzyme E2, and 20S proteasome subunits (i.e. critical components of the ubiquitin-proteasome proteolytic process) in skeletal muscle from such patients. Thus, in striking contrast with animal studies, glucocorticoids did not regulate the expression of muscle proteolytic genes in Cushing's syndrome. In humans, messenger RNA levels, for at least ubiquitin and proteasome subunits, are elevated in acute situations of muscle wasting, such as head trauma or sepsis. Because Cushing's syndrome is a chronic catabolic condition, we suggest that the lack of regulation of proteolytic genes in such patients may represent an adaptive regulatory mechanisms, preventing sustained increased protein breakdown and avoiding rapid muscle wasting.

Adult↗

PubMed1996

No alteration in gene expression of components of the ubiquitin-proteasome proteolytic pathway in dystrophin-deficient muscles.

Increased expression of critical components of the ubiquitin-dependent proteolytic pathway occurs in any muscle wasting condition so far studied in rodents where proteolysis rises. We have recently reported similar adaptations in head trauma patients [Mansoor et al. (1996) Proc. Natl. Acad. Sci. USA 93, 2714-2718]. We demonstrate here that the increased muscle protein breakdown seen in mdx mice only correlated with enhanced expression of m-calpain, a Ca(2+)-activated proteinase. By contrast, no change in mRNA levels for components of the ubiquitin-proteasome proteolytic process was seen in muscles from both mdx mice and Duchenne muscular dystrophy patients. Thus, gene expression of components of this pathway is not regulated in the chronic wasting that characterizes muscular dystrophy.

Adolescent↗

PubMed1996

Increased mRNA levels for components of the lysosomal, Ca2+-activated, and ATP-ubiquitin-dependent proteolytic pathways in skeletal muscle from head trauma patients.

The cellular mechanisms responsible for enhanced muscle protein breakdown in hospitalized patients, which frequently results in lean body wasting, are unknown. To determine whether the lysosomal, Ca2+-activated, and ubiquitin-proteasome proteolytic pathways are activated, we measured mRNA levels for components of these processes in muscle biopsies from severe head trauma patients. These patients exhibited negative nitrogen balance and increased rates of whole-body protein breakdown (assessed by [13C]leucine infusion) and of myofibrillar protein breakdown (assessed by 3-methylhistidine urinary excretion). Increased muscle mRNA levels for cathepsin D, m-calpain, and critical components of the ubiquitin proteolytic pathway (i.e., ubiquitin, the 14-kDa ubiquitin-conjugating enzyme E2, and proteasome subunits) paralleled these metabolic adaptations. The data clearly support a role for multiple proteolytic processes in increased muscle proteolysis. The ubiquitin proteolytic pathway could be activated by altered glucocorticoid production and/or increased circulating levels of interleukin 1beta and interleukin 6 observed in head trauma patients and account for the breakdown of myofibrillar proteins, as was recently reported in animal studies.

Adult↗

PubMed1996

Muscle wasting in a rat model of long-lasting sepsis results from the activation of lysosomal, Ca2+ -activated, and ubiquitin-proteasome proteolytic pathways.

We studied the alterations in skeletal muscle protein breakdown in long lasting sepsis using a rat model that reproduces a sustained and reversible catabolic state, as observed in humans. Rats were injected intravenously with live Escherichia coli; control rats were pair-fed to the intake of infected rats. Rats were studied in an acute septic phase (day 2 postinfection), in a chronic septic phase (day 6), and in a late septic phase (day 10). The importance of the lysosomal, Ca2+ -dependent, and ubiquitin-proteasome proteolytic processes was investigated using proteolytic inhibitors in incubated epitrochlearis muscles and by measuring mRNA levels for critical components of these pathways. Protein breakdown was elevated during the acute and chronic septic phases (when significant muscle wasting occurred) and returned to control values in the late septic phase (when wasting was stopped). A nonlysosomal and Ca2+ -independent process accounted for the enhanced proteolysis, and only mRNA levels for ubiquitin and subunits of the 20 S proteasome, the proteolytic core of the 26 S proteasome that degrades ubiquitin conjugates, paralleled the increased and decreased rates of proteolysis throughout. However, increased mRNA levels for the 14-kD ubiquitin conjugating enzyme E2, involved in substrate ubiquitylation, and for cathepsin B and m-calpain were observed in chronic sepsis. These data clearly support a major role for the ubiquitin-proteasome dependent proteolytic process during sepsis but also suggest that the activation of lysosomal and Ca2+ -dependent proteolysis may be important in the chronic phase.

Animals↗

PubMed1996

A high protein diet does not improve protein synthesis in the nonweight-bearing rat tibialis anterior muscle.

We recently demonstrated that a high protein intake partially prevented the decrease in protein synthesis in the atrophied dark soleus muscle of rats that were hindlimb suspended (HS) for 21 d. To study the possible role of protein intake in a muscle more representative of the whole musculature, we measured the effect of a high protein (HP) (30%) and a medium protein (MP) (15%) diet on protein synthesis in the pale fast-twitch tibialis anterior muscle of HS rats. The HS animals were suspended by the tail for 21 d so that only their front legs were able to rest on the floor. The fractional rate of protein synthesis (Ks) was determined in vivo using a flooding dose method. A significantly lower Ks (24-25%) was found in both HS-MP and HS-HP rats compared with their pair-fed control groups. Reduced Ks in HS-MP rats relative to their pair-fed controls resulted from a decrease in the translational efficiency (KRNA, 23%, P < 0.01), while the ratio of RNA to protein (Cs) was unaffected. In contrast, the decrease in KRNA was prevented in the HS-HP animals compared with their pair-fed controls (P < 0.05). Hindlimb suspension did not alter fiber type distribution in the tibialis anterior muscle. However, a higher proportion of intermediate and Type I fibers with a concomitant decrease in Type II fibers was observed in both CT and HS animals fed the HP diet compared with those fed the MP diet (P < 0.05). These data clearly establish that depressed protein synthesis contributes to altered protein accretion in fast-twitch muscles during long-term hindlimb suspension. Although the HP diet prevented the decrease in translational efficiency in muscles from HS rats, it neither sustained protein synthesis nor prevented the reduction in muscle growth. Thus, it seems very unlikely that a high protein diet had any beneficial effect on the overall musculature during weightlessness in rats.

Animals↗

PubMed1996

Gastrointestinal tract protein synthesis and mRNA levels for proteolytic systems in adult fasted rats.

We studied protein turnover in the gastrointestinal tract of adult fasted rats, since the mechanisms responsible for protein wasting in these tissues are poorly understood. Protein mass of stomach, small intestine, and colon decreased by 14-29 and 21-49% after 1 and 5 days of fasting, respectively. The fractional rate of in vivo protein synthesis (ks) was approximately 34% lower in the stomach after 1 and 5 days of fasting due to decreased capacity for protein synthesis (Cs). In small intestine and colon, ks was not different after 1 day, but was approximately 26% lower on day 5, mainly because of a reduction in Cs. Thus protein wasting in the stomach is primarily mediated by decreased protein synthesis but not in small intestine and colon during short-term fasting. To determine which proteolytic systems may be activated in the gut, we measured mRNA levels for critical components of the lysosomal (cathepsins B and D), Ca(2+)-activated (m-calpain), and ubiquitin-dependent (ubiquitin, 14-kDa ubiquitin-conjugating enzyme E2, and C8, and C9 proteasome subunits) proteolytic pathways. mRNA levels for most of these components increased during fasting, suggesting that a coordinated activation of multiple proteolytic systems contributed to intestinal protein wasting.

Animals↗

PubMed1996

Euglycemic hyperinsulinemia and hyperaminoacidemia decrease skeletal muscle ubiquitin mRNA in goats.

Insulin inhibits protein breakdown at the whole body level, but neither the tissues nor the proteolytic pathways on which insulin exerts its antiproteolytic effect are well characterized. We measured the effects of insulin on mRNA levels for cathepsin D and m-calpain (a lysosomal and Ca2(+)-dependent proteinase, respectively) and ubiquitin (a component of ubiquitin-dependent proteolysis) in skeletal muscle, skin, liver, and intestine. We used a 6-h hyperinsulinemic, euglycemic, and hyperaminoacidemic clamp in goats, a species in which insulin markedly inhibited whole body protein breakdown under similar conditions [S. Tesseraud, J. Grizard, E. Debras, I. Papet, Y. Bonnet, G. Bayle, and C. Champredon. Am. J. Physiol. 265 (Endocrinol. Metab. 28): E402-E413, 1993]. Hyperinsulinemia and hyperaminoacidemia had no effect on cathepsin D, m-calpain, and ubiquitin mRNA levels in liver, skin, and jejunum. In contrast, depressed ubiquitin mRNA levels were seen in skeletal muscle without any concomitant reduction in mRNA levels for cathepsin D, m-calpain, and other components of the ubiquitin-dependent proteolytic pathway. The reduced ubiquitin mRNA levels in skeletal muscle may represent a possible mechanism explaining the antiproteolytic effect of insulin in vivo.

Animals↗

PubMed1996

Glutamine synthetase induction by glucocorticoids is preserved in skeletal muscle of aged rats.

Glutamine synthetase (GS) is a glucocorticoid-inducible enzyme that has a key role for glutamine synthesis in muscle. We hypothesized that the glucocorticoid induction of GS could be altered in aged rats, because alterations in the responsiveness of some genes to glucocorticoids were reported in aging. We compared the glucocorticoid-induced GS in fast-twitch and slow-twitch skeletal muscles (tibialis anterior and soleus, respectively) and heart from adult (age 6-8 mo) and aged (age 22 mo) female rats. All animals received dexamethasone (Dex) in their drinking water (0.77 +/- 0.10 and 0.80 +/- 0.08 mg/day per adult and aged rat, respectively) for 5 days. Dex caused an increase in both GS activity and GS mRNA in fast-twitch and slow-twitch skeletal muscles from adult and aged rats. In contrast, Dex increased GS activity in heart of adult rats, without any concomitant change in GS mRNA levels. Furthermore, Dex did not affect GS activity in aged heart. Thus the responsiveness of GS to an excess of glucocorticoids is preserved in skeletal muscle but not in heart from aged animals.

Aging↗

PubMed1995

Sensitivity and protein turnover response to glucocorticoids are different in skeletal muscle from adult and old rats. Lack of regulation of the ubiquitin-proteasome proteolytic pathway in aging.

We studied glucocorticoid-induced muscle wasting and subsequent recovery in adult (7-mo-old) and old (22-mo-old) rats, since the increased incidence of various disease states may result in glucocorticoids hypersecretion in aging. Adult and old rats received dexamethasone in their drinking water and were then allowed to recover. Muscle wasting occurred more rapidly in old rats and the recovery of muscle mass was impaired, suggesting that glucocorticoids may be involved in the emergence of muscle atrophy with advancing age. According to measurements in incubated epitrochlearis muscles, dexamethasone-induced muscle wasting mainly resulted from increased protein breakdown in the adult, but from depressed protein synthesis in the aged animal. Increased expression of cathepsin D, m-calpain, and ubiquitin was observed in the muscles from both dexamethasone-treated adult and old rats. By contrast, the disappearance of the stimulatory effect of glucocorticoids on protein break-down in aging occurred along with a loss of ability of steroids to enhance the expression of the 14-kD ubiquitin carrier protein E2, which is involved in protein substrates ubiquitinylation, and of subunits of the 20 S proteasome (the proteolytic core of the 26 S proteasome that degrades ubiquitin conjugates). Thus, if glucocorticoids play any role in the progressive muscle atrophy seen in aging, this is unlikely to result from an activation of the ubiquitin-proteasome proteolytic pathway.

Aging↗

PubMed1994

Increased ATP-ubiquitin-dependent proteolysis in skeletal muscles of tumor-bearing rats.

Little information is available on proteolytic pathways responsible for muscle wasting in cancer cachexia. Experiments were carried out in young rats to demonstrate whether a small (< 0.3% body weight) tumor may activate the lysosomal, Ca(2+)-dependent, and/or ATP-ubiquitin-dependent proteolytic pathway(s) in skeletal muscle. Five days after tumor implantation, protein mass of extensor digitorum longus and tibialis anterior muscles close to a Yoshida sarcoma was significantly reduced compared to the contralateral muscles. According to in vitro measurements, protein loss totally resulted from increased proteolysis and not from depressed protein synthesis. Inhibitors of lysosomal and Ca(2+)-dependent proteases did not attenuate increased rates of proteolysis in the atrophying extensor digitorum longus. Accordingly, cathepsin B and B+L activities, and mRNA levels for cathepsin B were unchanged. By contrast, ATP depletion almost totally suppressed the increased protein breakdown. Furthermore, mRNA levels for ubiquitin, 14 kDa ubiquitin carrier protein E2, and the C8 or C9 proteasome subunits increased in the atrophying muscles. Similar adaptations occurred in the muscles from cachectic animals 12 days after tumor implantation. These data strongly suggest that the activation of the ATP-ubiquitin-dependent proteolytic pathway is mainly responsible for muscle atrophy in Yoshida sarcoma-bearing rats.

Animals↗

PubMed1994

Regulation of ATP-ubiquitin-dependent proteolysis in muscle wasting.

Protein breakdown plays a major role in muscle growth and atrophy. However, the regulation of muscle proteolysis by nutritional, hormonal and mechanical factors remains poorly understood. In this review, the methods available to study skeletal muscle protein breakdown, and our current understanding of the role of 3 major proteolytic systems that are well characterized in this tissue (ie the lysosomal, Ca(2+)-dependent and ATP-ubiquitin-dependent proteolytic pathways) are critically analyzed. ATP-ubiquitin-dependent proteolysis is discussed in particular since recent data strongly suggest that this pathway may be responsible for the loss of myofibrillar proteins in many muscle-wasting conditions in rodents. In striking contrast to either the lysosomal or the Ca(2+)-dependent processes, ATP-ubiquitin-dependent protein breakdown is systematically influenced by nutritional manipulation (fasting and dietary protein deficiency), muscle activity and disuse (denervation atrophy and simulated weightlessness), as well as pathological conditions (sepsis, cancer, trauma and acidosis). The hormonal control of this pathway, its possible substrates, rate-limiting step, and functional associations with other proteolytic systems are discussed.

Adenosine Triphosphate↗