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The effect of i.p. Cyst injection (arrow) on the body weight of healthy (A) and tumor-bearing (B) mice. Animals were treated once at day 15 and received either Cyst solution (OE and F; 20 mg/kg body weight) or saline solution (‚ and E; 20 ml/kg body weight). Inset, evolution of the tumor weight (in g versus days) in the Cyst-injected (f) and in the saline-injected () tumor-bearing mice. Bars, SE.
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Chemotherapy has cachectic effects, but it is unknown whether cytostatic agents alter skeletal muscle proteolysis. We hypothesized that chemotherapy-induced alterations in protein synthesis should result in the increased incidence of abnormal proteins, which in turn should stimulate ubiquitin-proteasome-dependent proteolysis. The effects of the nit...
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... lows Recovery in Tumor-bearing Mice. A single i.p. injection of Cyst at day 15 resulted in a rapid body weight loss in healthy animals within 5 days (Fig. 1A). Animals lost 5.0 0.5 g, i.e., 19% of their initial body weight. Changes in both EDL and tibialis anterior muscle mass paralleled body weight loss; muscle mass was not affected significantly by 1 day of Cyst treatment (i.e., at day 16), but both were reduced (P 0.005) at day 19 ( Fig. 2A). By contrast, mice were recovering in terms of ...
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... 5.0 0.5 g, i.e., 19% of their initial body weight. Changes in both EDL and tibialis anterior muscle mass paralleled body weight loss; muscle mass was not affected significantly by 1 day of Cyst treatment (i.e., at day 16), but both were reduced (P 0.005) at day 19 ( Fig. 2A). By contrast, mice were recovering in terms of body weight by day 26 (Fig. 1A), but muscle mass was still reduced with respect to the control animals ( Fig. 2A). An improvement in muscle mass was only seen at day 44 ( Fig. ...
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... 26 adenocarcinoma induced weight loss starting on day 10 and reached a maximum at day 17 (Fig. 1B). The body weights of the tumor-bearing mice then gradually increased, but this was almost totally accounted for by the development of the tumor (Fig. 1B, inset). Indeed, muscle wasting occurred very progressively (Fig. 2B). The Cyst injection at day 15 did not induce further body weight loss compared with the tumor group (Fig. 1B). By ...
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... 26 adenocarcinoma induced weight loss starting on day 10 and reached a maximum at day 17 (Fig. 1B). The body weights of the tumor-bearing mice then gradually increased, but this was almost totally accounted for by the development of the tumor (Fig. 1B, inset). Indeed, muscle wasting occurred very progressively (Fig. 2B). The Cyst injection at day 15 did not induce further body weight loss compared with the tumor group (Fig. 1B). By contrast, at day 19, muscle wasting was more pronounced in the Cyst-treated tumor- bearing mice than in the untreated tumor-bearing animals (Fig. 2B). Thus, in ...
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... at day 17 (Fig. 1B). The body weights of the tumor-bearing mice then gradually increased, but this was almost totally accounted for by the development of the tumor (Fig. 1B, inset). Indeed, muscle wasting occurred very progressively (Fig. 2B). The Cyst injection at day 15 did not induce further body weight loss compared with the tumor group (Fig. 1B). By contrast, at day 19, muscle wasting was more pronounced in the Cyst-treated tumor- bearing mice than in the untreated tumor-bearing animals (Fig. 2B). Thus, in this model, the cytostatic agent had an additive effect with tumor-induced muscle wasting. However, body weight loss after day 21 ( Fig. 1B) and muscle wasting after day 26 ...
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... weight loss compared with the tumor group (Fig. 1B). By contrast, at day 19, muscle wasting was more pronounced in the Cyst-treated tumor- bearing mice than in the untreated tumor-bearing animals (Fig. 2B). Thus, in this model, the cytostatic agent had an additive effect with tumor-induced muscle wasting. However, body weight loss after day 21 ( Fig. 1B) and muscle wasting after day 26 ( Fig. 2B) were reversed in the Cyst-treated tumor-bearing mice; therefore, a very significant improvement in muscle mass was detected at day 44 (P ...
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... Cyst-treated animals exhibited catch-up growth (e.g., growth more rapid than in healthy age-matched animals) from day 22 and for at least one week (Fig. 1). However, the body weights of both healthy and tumor-bearing Cyst-treated mice pla- teaued at 25 g and remained significantly lower than in controls (P 0.001; Fig. 1). Accordingly, the mass of both the EDL and tibialis anterior muscle also remained significantly lower than in control animals, even at day 44 (Fig. 2). Thus, there is a ...
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... Cyst-treated animals exhibited catch-up growth (e.g., growth more rapid than in healthy age-matched animals) from day 22 and for at least one week (Fig. 1). However, the body weights of both healthy and tumor-bearing Cyst-treated mice pla- teaued at 25 g and remained significantly lower than in controls (P 0.001; Fig. 1). Accordingly, the mass of both the EDL and tibialis anterior muscle also remained significantly lower than in control animals, even at day 44 (Fig. 2). Thus, there is a long- lasting growth defect in Cyst-treated mice that closely mimics the impairment in growth, which is commonly observed in chemother- apy-treated ...
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... Cured the Colon 26 Adenocarcinoma with a 100% Effi- cacy. The improvement in muscle mass seen between days 26 and 44 in Cyst-treated tumor-bearing mice (Fig. 2B) paralleled the progres- sive regression of the tumor, and no tumor tissue was detectable at day 44 (Fig. 1B, inset). However, at that time, the body weights of the cured tumor-bearing animals remained significantly lower (P 0.001) than in saline-injected control mice, as did the healthy Cyst-treated animals (Fig. 1). Cyst cured the colon 26 adenocarci- noma with a 100% efficacy, and no recurrence of tumor was seen up to 80 days after the treatment ...
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... tumor-bearing mice (Fig. 2B) paralleled the progres- sive regression of the tumor, and no tumor tissue was detectable at day 44 (Fig. 1B, inset). However, at that time, the body weights of the cured tumor-bearing animals remained significantly lower (P 0.001) than in saline-injected control mice, as did the healthy Cyst-treated animals (Fig. 1). Cyst cured the colon 26 adenocarci- noma with a 100% efficacy, and no recurrence of tumor was seen up to 80 days after the treatment (data not ...
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Citations
... The UPS is a critical system activated during muscle wasting and is responsible for directing proteins to be degraded in the proteasome, including contractile components of skeletal muscle (29). We demonstrated that FOR restores Akt/FoxO3 signaling impaired by DOX treatment, a pathway that has a central role in UPS regulation. ...
Background
Even though doxorubicin (DOX) chemotherapy promotes intense muscle wasting, this drug is still widely used in clinical practice due to its remarkable efficiency in managing cancer. On the other hand, intense muscle loss during the oncological treatment is considered a bad prognosis for the disease’s evolution and the patient’s quality of life. In this sense, strategies that can counteract the muscle wasting induced by DOX are essential. In this study, we evaluated the effectiveness of formoterol (FOR), a β2-adrenoceptor agonist, in managing muscle wasting caused by DOX.
Methods and results
To evaluate the effect of FOR on DOX-induced muscle wasting, mice were treated with DOX (2.5 mg/kg b.w., i.p. administration, twice a week), associated or not to FOR treatment (1 mg/kg b.w., s.c. administration, daily). Control mice received vehicle solution. A combination of FOR treatment with DOX protected against the loss of body weight (p<0.05), muscle mass (p<0.001), and grip force (p<0.001) promoted by chemotherapy. FOR also attenuated muscle wasting (p<0.01) in tumor-bearing mice on chemotherapy. The potential mechanism by which FOR prevented further DOX-induced muscle wasting occurred by regulating Akt/FoxO3a signaling and gene expression of atrogenes in skeletal muscle.
Conclusions
Collectively, our results suggest that FOR can be used as a pharmacological strategy for managing muscle wasting induced by DOX. This study provides new insights into the potential therapeutic use of FOR to improve the overall wellbeing of cancer patients undergoing DOX chemotherapy.
... Several other chemotherapeutic agents have been investigated for their impact on skeletal muscle, albeit to a far lesser extent than DOX, CDDP, and 5FU. Distinct from platinum-based alkylating agents, chemotherapies arising from the alternative alkylating agent classes such as nitrosourea (i.e., cystemustine (CMN)) and nitrogen mustard (i.e., cyclophosphamide (CYP)) have also been investigated for their effect on skeletal muscle [73,[105][106][107]. Interestingly, in cancer-free mice, CMN acutely reduces body mass, and, while post-chemotherapy catch-up growth is evident, skeletal muscle mass does not completely recover [106]. ...
... Distinct from platinum-based alkylating agents, chemotherapies arising from the alternative alkylating agent classes such as nitrosourea (i.e., cystemustine (CMN)) and nitrogen mustard (i.e., cyclophosphamide (CYP)) have also been investigated for their effect on skeletal muscle [73,[105][106][107]. Interestingly, in cancer-free mice, CMN acutely reduces body mass, and, while post-chemotherapy catch-up growth is evident, skeletal muscle mass does not completely recover [106]. However, in tumour-bearing mice, the effect of CMN manifests differently. ...
... However, in tumour-bearing mice, the effect of CMN manifests differently. CMN treatment (10 days) reduces skeletal muscle mass, albeit, paradoxically, concurrent with enhanced protein synthesis and reduced proteasome-dependent proteolysis at the molecular level [105,106]. These data perhaps reflect an ongoing, yet unsuccessful, attempt to recover skeletal muscle mass in response to CMN treatment. ...
Cancer cachexia is a debilitating multi-factorial wasting syndrome characterised by severe skeletal muscle wasting and dysfunction (i.e., myopathy). In the oncology setting, cachexia arises from synergistic insults from both cancer–host interactions and chemotherapy-related toxicity. The majority of studies have surrounded the cancer–host interaction side of cancer cachexia, often overlooking the capability of chemotherapy to induce cachectic myopathy. Accumulating evidence in experimental models of cachexia suggests that some chemotherapeutic agents rapidly induce cachectic myopathy, although the underlying mechanisms responsible vary between agents. Importantly, we highlight the capacity of specific chemotherapeutic agents to induce cachectic myopathy, as not all chemotherapies have been evaluated for cachexia-inducing properties—alone or in clinically compatible regimens. Furthermore, we discuss the experimental evidence surrounding therapeutic strategies that have been evaluated in chemotherapy-induced cachexia models, with particular focus on exercise interventions and adjuvant therapeutic candidates targeted at the mitochondria.
... The chemotherapy used in the myeloablative procedure can, by itself, alter the protein synthesis, generating anomalous proteins that are later cleaved by the ubiquitin proteasome pathway. This supports the hypothesis that the use of these drugs is directly linked to a reduction in muscle units, thus reducing muscle strength (Tilignac et al, 2002). However, these effects need time to manifest, therefore it would be unreasonable to attribute the reduction of muscle function observed in the patients assessed after their medullary recovery in the present study to this proteolytic mechanism. ...
Background/Aims
The negative impact caused by haematopoietic stem cell transplantation still requires further investigation. This study aims to investigate the effects of this procedure on skeletal muscle strength, functional performance and fatigue sensation in the hospitalisation phase.
Methods
This prospective cohort study aimed to assess physical performance by measuring ventilatory muscle strength, peripheral muscle strength and fatigue in patients who underwent haematopoietic stem cell transplantation.
Results
The sample consisted of 30 patients of both sexes (63% men) with a mean age of 48.6 ± 13.2 years. Maximal inspiratory pressure and expiratory pressure decreased by 19% and 16%, respectively (P<0.001). There was a 16% reduction in handgrip strength in the second assessment (P<0.001), as well as a reduction of 30.6% in the 30-Second Chair Stand Test (P<0.001). The fatigue test score increased exponentially (60%) (P<0.001). Individuals with worse results in the 30-Second Chair Stand Test remained hospitalised for a longer period than those with better results (P=0.024).
Conclusions
This study concluded that after the transplantation of haematopoietic stem cells there was a relevant reduction in the results of the applied tests, as well as an increase in fatigue.
... CHT induced body composition changes cannot be excluded. Nevertheless, in the colon 26 adenocarcinoma murine model, fluoropyrimidines would seem to slow the breakdown of muscle proteins by the UPS [30,31]. These findings could be considered to understand the preservation of endurance despite significant weight loss in patients with PS 0-2. ...
Background
Muscle function and its correlation with body composition and weight loss have not been studied deeply in pancreas and gastrointestinal cancers. This research aims to determine the skeletal muscle function and its relationship with body compartments, significant weight loss, and performance status (ECOG) 0-2 in a population with advanced digestive cancers.
Methods
A cross-sectional study was designed to determine the relationship between muscular function, weight loss, and body composition. Patients with advanced digestive adenocarcinomas were evaluated. Muscle strength was examined by hand grip technique and body composition by bioimpedance analysis. Values of hemoglobin and albumin were measured in plasma.
Results
A sample of 81 patients was included. They had adenocarcinoma of stomach (n = 9), pancreas (n = 28), or colorectum (n = 44). With regard to skeletal muscle function, sub-maximal strength increased when percentage of weight loss decreased (p = 0.002) or when any of the following variables increased: skeletal muscle (p < 0.001), waist-hip ratio (p < 0.001), body surface area (p < 0.001), and body mass index (p = 0.001). According to multivariate analysis of these variables, only percentage of weight loss and skeletal muscle remained statistically significant. Endurance had no correlation with any of the variables. Higher weight loss was found in tumors of the upper tract (stomach and pancreas) in comparison with those of the lower tract (colorectal) (p = 0.005).
Conclusions
In advanced digestive cancer, sub-maximal strength correlated inversely with weight loss and directly with skeletal muscle such as in lung and head and neck cancers. On the other hand, endurance had no correlation with any of the variables considered.
... Strikingly, cisplatin alone was seen to regulate muscle atrophy, which was independent of the commonly implicated ubiquitin proteasome system» (Damrauer et al.). 21 It is worth noting that then another group had reported opposite findings, i.e. that chemotherapy inhibits protein breakdown and promotes protein synthesis 24,25 , however, both studies showed that cisplatin induced body weight loss and muscle wasting in healthy mice, suggesting that chemotherapy does indeed induce muscle loss. Very likely, cisplatin triggers multiple responses in muscle tissue, which ultimately lead to muscle fiber atrophy while the role of protein ubiquitination and proteasomemediated degradation remains controversial (see also below). ...
The majority of cancers are associated to cachexia, a severe form of weight loss mostly accounted for by skeletal muscle wasting. Cancer patients are often treated with chemotherapy, whose side effects are at times neglected or underestimated. Paradoxically, chemotherapy itself can induce muscle wasting with severe, cancer-independent effects on muscle homeostasis. Since muscle wasting is a primary marker of poor prognosis for cancer patients and negatively affects their quality of life, the systemic consequences of chemotherapy in this context must be fully characterized and taken into account. Ten years ago a precursor study in an animal cancer model was published in the European Journal of Translation Myology (back then, Basic and Applied Myology), highlighting that the side effects of chemotherapy include muscle wasting, possibly mediated by NF-κB activation. This paper, entitled «Chemotherapy-induced muscle wasting: association with NF-κB and cancer cachexia», is now being reprinted for the inaugural issue of the «Ejtm Seminal Paper Series». In this short review we discuss those results in the light of the most recent advances in the study of chemotherapy-induced muscle wasting.
... The former is redefined as >10% body weight loss for simplicity. In Table 1A, the carcass weight of the tumor-bearing mice (TB) is lighter than that of control mice [26]. In terms of tumor weight, the severe cachectic mice are 2-fold heavier than the moderate (Table 1A). ...
... Since the level of phospholipids (PLs) is a metabolic index of endogenous or dietary fatty acids [37], the level of plasma PLs was therefore determined to estimate n-3 fatty acids in the blood of mice. As shown in Figure 5C, the PLs level in tumorbearing mice under chemotherapy (TD) is lower than that of normal mice [26]. In contrast, the level of PLs in mice supplemented with fish oil and selenium yeast is higher. ...
... The level of myostatin increased earlier than that of IL-6 in P19 muscle cells treated with docetaxel ( Figure 4D), suggesting that myostatin interacts with circulating inflammatory cytokines. This result agrees with the study where C2C12 myotubules treated with myostatin significantly increased IL-6 mRNA in muscle cells [45], while it disagrees with some published results that favor the proteasomedependent muscle proteolysis [26,46]. In general, skeletal muscle atrophy results from overexpression of TNF-α and myostatin, which up-regulates calcium-activated and ubiquitin-proteasome systems in tumor mice. ...
Chemotherapy can cause cachexia, which is manifested by weight loss, inflammation and muscle atrophy. However, the mechanisms of tumor and chemotherapy on skeletal muscle proteolysis, however, remained unclear. In this report, we demonstrated that tumor-induced myostatin in turn induced TNF-α, thus activating calcium-dependent and proteasomal protein degradation. Chemotherapy activated myostatin-mediated proteolysis and muscle atrophy by elevating IL-6. In tumor-bearing mice under chemotherapy, supplementation with fish oil and selenium prevented a rise in IL-6, TNF-α and myostatin and muscle atrophy. The findings presented here allow us to better understand the molecular basis of cancer cachexia and potentiate nutrition supplementation in future cancer chemotherapy.
... Muscle mass recovery after unloading is also dependent on the generation of a sustained positive nitrogen balance which results from normalization of changes in protein metabolism associated with an increased protein synthesis, decreased proteolysis, or simultaneous changes in both processes. Thus, during recovery in adults, muscle protein synthesis was increased (Booth 1982) and muscle protein breakdown was down-regulated, normalized or increased according to the model of immobilization used (Tilignac et al. 2002;Taillandier et al. 2003;Minnaard et al. 2005;Vazeille et al. 2008), which allowed a muscle mass recovery over time after reloading. We have shown that during ageing, mechanisms of casting-induced-atrophy were similar to those observed in adult animals, i.e. an increased ubiquitin-proteasome-dependent proteolysis and apoptosis in skeletal muscle (Magne et al. 2011). ...
Key points During ageing, there is a lack of recovery of muscle mass following immobilization.
We showed, in old rats, an ‘anabolic resistance’ of muscle protein synthesis to food intake during immobilization and only a slight increase of protein synthesis during the recovery, which explain a poor muscle nitrogen balance that is insufficient to induce a muscle mass gain.
A supplementation with free leucine, an essential amino acid known to stimulate muscle protein metabolism, was efficient in inducing a greater anabolism but failed to induce muscle mass recovery.
This discrepancy was explained by a ‘desynchronization’ between the leucine signal and amino acids coming from dietary protein digestion.
An induction of a larger increase and a longer availability of amino acids in the postprandial state with rich‐protein leucine (i.e. whey) and high protein diets were efficient in inducing a muscle mass recovery after immobilization.
... Muscle mass recovery after unloading is also dependent on the generation of a sustained positive nitrogen balance which results not only from normalization of changes in protein metabolism but also from increased protein synthesis, decreased proteolysis, or simultaneous changes in both processes. Thus, during recovery in adults, muscle protein synthesis was increased et muscle protein breakdown was down-regulated, normalized or increased according to the model of immobilization used (Tilignac et al. 2002, Minnaard et al. 2005, Vazeille et al. 2008) which allowed a muscle mass recovery over time after reloading. We have shown that during aging unloading-induced-atrophy was also due to an increased ubiquitin-proteasome-dependent proteolysis and apoptosis in skeletal muscle, but the lack of muscle mass recovery we recorded was not due to a sustained activation of these pathways after reloading as they were rapidly normalized during the recovery period. ...
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... Chemotherapeutic drugs, such as cisplatin and ifosfamide [19], are known to kill the bulk of tumors by down-regulating ubiquitin-proteasome-dependent proteolysis [20]. However, they also lead to the propagation of CSCs [18]. ...
... Down-regulation of ubiquitin-proteasome-dependent proteolysis was observed in response to various chemotherapeutic agents, such as cisplatin [19], ifosfamide [19] and Bortezomib [32]. Recent findings showed that chemotherapeutic drugs, such as cisplatin, can also lead to propagation of CSCs [18]. ...
... Down-regulation of ubiquitin-proteasome-dependent proteolysis was observed in response to various chemotherapeutic agents, such as cisplatin [19], ifosfamide [19] and Bortezomib [32]. Recent findings showed that chemotherapeutic drugs, such as cisplatin, can also lead to propagation of CSCs [18]. ...
Cancer stem cells (CSCs) are a small subset of cancer cells capable of self-renewal and tumor maintenance. Eradicating cancer stem cells, the root of tumor origin and recurrence, has emerged as one promising approach to improve lung cancer survival. Cancer stem cells are reported to reside in the side population (SP) of cultured lung cancer cells. We report here the coexistence of a distinct population of non-SP (NSP) cells that have equivalent self-renewal capacity compared to SP cells in a lung tumor sphere assay. Compared with the corresponding cells in monolayer cultures, lung tumor spheres, formed from human non-small cell lung carcinoma cell lines A549 or H1299, showed marked morphologic differences and increased expression of the stem cell markers CD133 and OCT3/4. Lung tumor spheres also exhibited increased tumorigenic potential as only 10,000 lung tumor sphere cells were required to produce xenografts tumors in nude mice, whereas the same number of monolayer cells failed to induce tumors. We also demonstrate that lung tumor spheres showed decreased 26S proteasome activity compared to monolayer. By using the ZsGreen-cODC (C-terminal sequence that directs degradation of Ornithine Decarboxylase) reporter assay in NSCLC cell lines, only less than 1% monolayer cultures were ZsGreen positive indicating low 26S proteasome, whereas lung tumor sphere showed increased numbers of ZsGreen-positive cells, suggesting the enrichment of CSCs in sphere cultures.
... After 30 min of preincubation, muscles were transferred to a fresh medium of identical composition, saturated with an O 2 /CO 2 (19/1) gas mixture and incubated further for 1 h at 37°C. Rates of protein breakdown were measured by following the rates of tyrosine release into the medium in the presence of 0.5 mmol/L cycloheximide to block protein synthesis [19]. The contribution of lysosomal and Ca 2+ -dependent proteases and of proteasome to the rates of overall proteolysis was determined as described [19]. ...
... Rates of protein breakdown were measured by following the rates of tyrosine release into the medium in the presence of 0.5 mmol/L cycloheximide to block protein synthesis [19]. The contribution of lysosomal and Ca 2+ -dependent proteases and of proteasome to the rates of overall proteolysis was determined as described [19]. When measuring proteasome-dependent proteolysis, skeletal muscles were incubated in the presence of lysosomal and Ca 2+ -dependent protease inhibitors because the proteasome inhibitor MG132 also inhibits cysteine proteases (i.e., cathepsin B, H and L, and calpains) [19]. ...
... The contribution of lysosomal and Ca 2+ -dependent proteases and of proteasome to the rates of overall proteolysis was determined as described [19]. When measuring proteasome-dependent proteolysis, skeletal muscles were incubated in the presence of lysosomal and Ca 2+ -dependent protease inhibitors because the proteasome inhibitor MG132 also inhibits cysteine proteases (i.e., cathepsin B, H and L, and calpains) [19]. Protein degradation was expressed in nanomoles of tyrosine released into the medium per milligram of protein per hour. ...
Skeletal muscle proteolysis is inhibited by oral feeding in the young and mature but not in the elderly. However, the proteolytic pathway(s) responsible for the decreased muscle proteolysis in the postprandial (PP) state is (are) unknown in the young. Moreover, muscle proteolysis is inhibited by both insulin (INS) and amino acids (AA) in vitro, but their respective roles on specific proteolytic pathways in vivo remain to be elucidated. The aim of this study was to investigate the respective role of INS and AA on the inhibition of proteolytic pathways in the PP state in skeletal muscles from young, mature and old rats. Rats were fed over 1 h either a 25% (AA+) or a 0% (AA-) amino acid/protein meal. In each nutritional condition, PP insulin secretion was maintained (AA+/INS+ and AA-/INS+) or blocked (AA+/INS- and AA-/INS-) with diazoxide injections. We report that the PP inhibition of proteolysis in young rats was mediated by the increased INS secretion and resulted from a down-regulation of both lysosomal and Ca(2+)-dependent proteolysis. Moreover, our data showed that proteasome activities are inhibited by either INS or AA in mature rats, whereas they become selectively insensitive to AA in old rats. In conclusion, the present work provides direct evidence that the lack of PP regulation of proteasome-dependent proteolysis in old rats resulted from a selective resistance to AA.
