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Branched Chain Amino Acids and Muscle Atrophy Protection

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Abstract

A variety of diseases and conditions result in muscle atrophy. Muscle atrophy causes a decrease of mobility, increased susceptibility to injuries and reduced Quality of Life (QOL). The various types of muscle atrophy are due to increased protein breakdown, decreased protein synthesis or both. Muscle mass is maintained by the balance between muscle protein synthesis and degradation. To prevent muscle atrophy, several types of intervention have been tried. Branched-chain amino acid (BCAA) administration is one of the interventions because BCAAs have been reported to stimulate protein synthesis and attenuate protein degradation in muscles. BCAAs are components of proteins that also function as signals that regulate cellular signaling pathways activated in the protein synthesis and protein degradation. In this review, the regulatory functions of the BCAAs in cellular signaling are discussed first, and the effects of the BCAAs on several types of muscle atrophy in human and animals are described thereafter.

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Background: Much interest has been focused on nutritional treatment of sarcopenia, loss of muscle mass and performance associated to aging; however, its benefits are unclear. Objective: To analyze the relevance of nutritional treatment of sarcopenia and assess the effects of supplementation on muscle mass and function within the aged population. Methods: We searched Medline and the Cochrane Library for controlled trials published between 1991 and 2012. We have assessed the quality, type of intervention, the cohort used, the way muscle mass was measured, and the outcomes of the various studies. Results: We have included 17 studies, with a total of 1287 patients, aged between 65 and 85 on average. An improvement in muscle mass was proven, whether measured with bioelectrical impedance analysis or dual energy x-ray absorptiometry, and an improvement in strength was also proven. Conclusion: Nutritional supplementation is effective in the treatment of sarcopenia in old age, and its positive effects increase when associated with physical exercise. The main limitation of this treatment is lack of long-term adherence. A healthy diet associated with a physically active lifestyle and possibly with aerobic exercise are the basis of healthy aging, which is the aim of all doctors treating aged people must seek.
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Protein supplementation has been proposed as an effective dietary strategy to augment the skeletal muscle adaptive response to prolonged resistance-type exercise training in elderly people. Our objective was to assess the impact of protein supplementation on muscle mass, strength, and physical performance during prolonged resistance-type exercise training in frail elderly men and women. A randomized, double-blind, placebo-controlled trial with 2 arms in parallel among 62 frail elderly subjects (78 ± 1 year). These elderly subjects participated in a progressive resistance-type exercise training program (2 sessions per week for 24 weeks) during which they were supplemented twice daily with either protein (2 ∗ 15 g) or a placebo. Lean body mass (DXA), strength (1-RM), and physical performance (SPPB) were assessed at baseline, and after 12 and 24 weeks of intervention. Lean body mass increased from 47.2 kg (95% CI, 43.5-50.9) to 48.5 kg (95% CI, 44.8-52.1) in the protein group and did not change in the placebo group (from 45.7 kg, 95% CI, 42.1-49.2 to 45.4 kg, 95% CI, 41.8-48.9) following the intervention (P value for treatment × time interaction = .006). Strength and physical performance improved significantly in both groups (P = .000) with no interaction effect of dietary protein supplementation. Prolonged resistance-type exercise training represents an effective strategy to improve strength and physical performance in frail elderly people. Dietary protein supplementation is required to allow muscle mass gain during exercise training in frail elderly people. Trial Registration:clinicaltrials.gov identifier: NCT01110369.
Article
A spherical reflector illuminated by a point source is found to be capable of launching an electromagnetic missile. Since the surfaces of the reflector are not complete spherical surfaces, the problem cannot be solved by simple boundary matching. The electromagnetic fields have to be solved in three regions separately. The general solutions are matched on the boundaries to obtain a set of coefficient equations. Under the conditions for an electromagnetic missile, the coefficient equations are solved asymptotically. The evaluation of the Poynting vector shows that the energy radiated from the reflector has the same slow rate of decay as for the spherical lens.
Article
To evaluate the effectiveness of exercise and amino acid supplementation in enhancing muscle mass and strength in community-dwelling elderly sarcopenic women. Randomized controlled trial. Urban community in Tokyo, Japan. One hundred fifty-five women aged 75 and older were defined as sarcopenic and randomly assigned to one of four groups: exercise and amino acid supplementation (exercise + AAS; n = 38), exercise (n = 39), amino acid supplementation (AAS; n = 39), or health education (HE; n = 39). The exercise group attended a 60-minute comprehensive training program twice a week, and the AAS group ingested 3 g of a leucine-rich essential amino acid mixture twice a day for 3 months. Body composition was determined using bioelectrical impedance analysis. Data from interviews and functional fitness parameters such as muscle strength and walking ability were collected at baseline and after the 3-month intervention. A significant group × time interaction was seen in leg muscle mass (P = .007), usual walking speed (P = .007), and knee extension strength (P = .017). The within-group analysis showed that walking speed significantly increased in all three intervention groups, leg muscle mass in the exercise + AAS and exercise groups, and knee extension strength only in the exercise + AAS group (9.3% increase, P = .01). The odds ratio for leg muscle mass and knee extension strength improvement was more than four times as great in the exercise + AAS group (odds ratio = 4.89, 95% confidence interval = 1.89-11.27) as in the HE group. The data suggest that exercise and AAS together may be effective in enhancing not only muscle strength, but also combined variables of muscle mass and walking speed and of muscle mass and strength in sarcopenic women.
Article
The mammalian target of rapamycin (mTOR) is an evolutionarily conserved serine/threonine protein kinase that regulates numerous cellular processes including cell growth, proliferation, cell cycle, and autophagy. mTOR forms two different multi-protein complexes referred to as mTOR complex 1 (mTORC1) and mTORC2, and each complex exerts distinct functions exclusively. mTORC1 activity is sensitive to the selective inhibitor rapamycin, whereas mTORC2 is resistant. mTORC1 is regulated by many intra- and extra-cellular cues such as growth factors, nutrients, and energy-sensing signals, while mTORC2 senses ribosome maturation and growth factor signaling. This review focuses on current understandings by which mTORC1 pathway senses cellular nutrient availability for its activation.
Article
In the postabsorptive state, certain tissues, including the brain, require glucose as the sole source of energy. After an overnight fast, hepatic glycogen stores are depleted, and gluconeogenesis becomes essential for preventing life-threatening hypoglycemia. Mice with a targeted deletion of KLF15, a member of the Krüppel-like family of transcription factors, display severe hypoglycemia after an overnight (18 hr) fast. We provide evidence that defective amino acid catabolism promotes the development of fasting hypoglycemia in KLF15-/- mice by limiting gluconeogenic substrate availability. KLF15-/- liver and skeletal muscle show markedly reduced mRNA expression of amino acid-degrading enzymes. Furthermore, the enzymatic activity of alanine aminotransferase (ALT), which converts the critical gluconeogenic amino acid alanine into pyruvate, is decreased (approximately 50%) in KLF15-/- hepatocytes. Consistent with this observation, intraperitoneal injection of pyruvate, but not alanine, rescues fasting hypoglycemia in KLF15-/- mice. We conclude that KLF15 plays an important role in the regulation of gluconeogenesis.
Article
Maintenance of skeletal muscle mass relies on the dynamic balance between anabolic and catabolic processes and is important for motility, systemic energy homeostasis, and viability. We identified direct target genes of the glucocorticoid receptor (GR) in skeletal muscle, i.e., REDD1 and KLF15. As well as REDD1, KLF15 inhibits mTOR activity, but via a distinct mechanism involving BCAT2 gene activation. Moreover, KLF15 upregulates the expression of the E3 ubiquitin ligases atrogin-1 and MuRF1 genes and negatively modulates myofiber size. Thus, GR is a liaison involving a variety of downstream molecular cascades toward muscle atrophy. Notably, mTOR activation inhibits GR transcription function and efficiently counteracts the catabolic processes provoked by glucocorticoids. This mutually exclusive crosstalk between GR and mTOR, a highly coordinated interaction between the catabolic hormone signal and the anabolic machinery, may be a rational mechanism for fine-tuning of muscle volume and a potential therapeutic target for muscle wasting.
Article
Maintenance of skeletal muscle mass depends on the equilibrium between protein synthesis and protein breakdown; diminished functional demand during unloading breaks this balance and leads to muscle atrophy. The current study analyzed time-course alterations in regulatory genes and proteins in the unloaded soleus muscle and the effects of branched-chain amino acid (BCAA) supplementation on muscle atrophy and abundance of molecules that regulate protein turnover. Short-term (6 days) hindlimb suspension of rats resulted in significant losses of myofibrillar proteins, total RNA, and rRNAs and pronounced atrophy of the soleus muscle. Muscle disuse induced upregulation and increases in the abundance of the eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1), increases in gene and protein amounts of two ubiquitin ligases (muscle RING-finger protein 1 and muscle atrophy F-box protein), and decreases in the expression of cyclin D1, the ribosomal protein S6 kinase 1, the mammalian target of rapamycin (mTOR), and ERK1/2. BCAA addition to the diet did not prevent muscle atrophy and had no apparent effect on regulators of proteasomal protein degradation. However, BCAA supplementation reduced the loss of myofibrillar proteins and RNA, attenuated the increases in 4E-BP1, and partially preserved cyclin D1, mTOR and ERK1 proteins. These results indicate that BCAA supplementation alone does not oppose protein degradation but partly preserves specific signal transduction proteins that act as regulators of protein synthesis and cell growth in the non-weight-bearing soleus muscle.
Article
Amino acids are required for activation of the mammalian target of rapamycin (mTOR) kinase which regulates protein translation, cell growth, and autophagy. Cell surface transporters that allow amino acids to enter the cell and signal to mTOR are unknown. We show that cellular uptake of L-glutamine and its subsequent rapid efflux in the presence of essential amino acids (EAA) is the rate-limiting step that activates mTOR. L-glutamine uptake is regulated by SLC1A5 and loss of SLC1A5 function inhibits cell growth and activates autophagy. The molecular basis for L-glutamine sensitivity is due to SLC7A5/SLC3A2, a bidirectional transporter that regulates the simultaneous efflux of L-glutamine out of cells and transport of L-leucine/EAA into cells. Certain tumor cell lines with high basal cellular levels of L-glutamine bypass the need for L-glutamine uptake and are primed for mTOR activation. Thus, L-glutamine flux regulates mTOR, translation and autophagy to coordinate cell growth and proliferation.
Article
The aim of this study was to elucidate the effects of long-term intake of leucine in dietary protein malnutrition on muscle protein synthesis and degradation. A reduction in muscle mass was suppressed by leucine-supplementation (1.5% leucine) in rats fed protein-free diet for 7 days. Furthermore, the rate of muscle protein degradation was decreased without an increase in muscle protein synthesis. In addition, to elucidate the mechanism involved in the suppressive effect of leucine, we measured the activities of degradation systems in muscle. Proteinase activity (calpain and proteasome) and ubiquitin ligase mRNA (Atrogin-1 and MuRF1) expression were not suppressed in animals fed a leucine-supplemented diet, whereas the autophagy marker, protein light chain 3 active form (LC3-II), expression was significantly decreased. These results suggest that the protein-free diet supplemented with leucine suppresses muscle protein degradation through inhibition of autophagy rather than protein synthesis.
Article
Sepsis is associated with severe muscle wasting. Mechanisms responsible for sepsis-induced alterations in muscle protein metabolism were investigated in vivo and compared with changes induced by nonseptic inflammation. The rate of protein synthesis in mixed hindlimb muscles was not altered in inflammation but was inhibited 50% in sepsis. This inhibition did not result from a decreased RNA content. Instead, the translational efficiency was significantly reduced by 50% in skeletal muscle of septic animals compared with control. The effect of sepsis to lower the rate of protein synthesis was further examined using individual muscles containing different fiber types. Both the protein concentration and protein synthetic rate in fast-twitch muscles were reduced by sepsis, whereas neither of these parameters was affected in slow-twitch muscles or heart. The decreased translational efficiency did not result from a change in the rate of peptide-chain elongation. Instead, the sepsis-induced inhibition of protein synthesis resulted from a restraint in peptide-chain initiation because sepsis caused a 1.6-fold increase in free ribosomal subunits. Overall, sepsis, but not inflammation, caused an inhibition of protein synthesis primarily in muscles composed of fast-twitch fibers. The mechanism involved in the reduced rates of protein synthesis in muscles resulted from an inhibition of peptide-chain initiation, with no change in peptide-chain elongation.
Article
Exposure to conditions of weightlessness has been associated with decrements in muscle mass and strength. The present studies were undertaken to determine muscle responses at the cellular level. Male Sprague-Dawley rats (360-410 g) were exposed to 7 days of weightlessness during the Spacelab-3 shuttle flight (May 1985). Animals were killed 12 h postflight, and soleus (S), gastrocnemius (G), and extensor digitorum longus (EDL) muscles were excised. Muscle protein, RNA, and DNA were extracted and quantified. Differential muscle atrophy was accompanied by a significant (P less than 0.05) reduction in total protein only in S muscles. There were no significant changes in protein concentration (mg/g) in the muscles examined. In S muscles from flight animals, sarcoplasmic protein accounted for a significantly greater proportion of total protein that in ground controls (37.5 vs. 32.5%). Tissue concentrations (nmol/g) of asparagine-aspartate, glutamine-glutamate, glycine, histidine, and lysine were significantly reduced (from 17 to 63%) in S muscles from flight animals, but only glutamine-glutamate levels were decreased in the G and EDL. Muscle DNA content (microgram) was unchanged in the tissues examined, but S muscle DNA concentration (micrograms/mg) increased 27%. RNA content (micrograms) was significantly (P less than 0.025) reduced in S (-28%) and G(-22%) muscles following spaceflight. These results identify specific alterations in rat skeletal muscle during short term (7-day) exposure to weightlessness and compare favorably with observations previously obtained from ground-based suspension simulations.
Article
The purpose of this study was to investigate alterations in structural and functional properties in the soleus (SOL) and extensor digitorum longus (EDL) muscles of rats after 1, 2, and 5 wk of tail suspension. Maximal O2 uptake was 19% lower after 5 wk suspension. Loss of muscle mass was greater in SOL (63%) than in EDL (22%) muscle. A reduction of type I distribution was accompanied by an increase of intermediate fiber subgroups (int I in SOL, int II in EDL). The cross-sectional area of all three fiber types was reduced by hypokinesia. The decrease in capillaries per fiber in SOL was greater than the decrease in citrate synthase and 3-hydroxyacyl-CoA dehydrogenase activities after 5 wk. No alteration in lactate dehydrogenase activity was noted. In EDL, no changes in fiber area, capillarization, and enzymatic activities occurred. Energy charge remained unchanged (0.91) whatever the muscle. These results suggest that type I fibers showed an earlier and greater susceptibility than type II fibers to suspension which is also accompanied by a decreased aerobic capacity.
Article
Myofibril disintegration in rat skeletal muscle fibers denervated at early stages of development is accompanied by increase in number and size of lysosomes with concomitant hypertrophy of the Golgi apparatus. Dense bodies, cuplike bodies, multivesicular bodies, and digestive vacuoles containing amorphous material are especially conspicuous in the denervated muscle cells. Autophagic vacuoles containing recognizable cytoplasmic components are also seen, but intact myofilaments are never found segregated within autophagic vacuoles. Acid phosphatase and aryl sulfatase activities are present, though not consistently, in the different lysosomal structures. Diffuse reaction product is never observed in preparations incubated for acid hydrolase activity. The findings suggest that myofibril disintegration in the course of denervation atrophy of skeletal muscles does not result from lysosomal activation, but is presumably initiated by extralysosomal mechanisms. On the other hand, it appears possible that the accumulation of degradation products arising from the breakdown of the myofibrils in the ground cytoplasm may stimulate lysosome formation and induce autophagic processes.
Article
Spaceflight (SF) has been shown to cause skeletal muscle atrophy; a loss in force and power; and, in the first few weeks, a preferential atrophy of extensors over flexors. The atrophy primarily results from a reduced protein synthesis that is likely triggered by the removal of the antigravity load. Contractile proteins are lost out of proportion to other cellular proteins, and the actin thin filament is lost disproportionately to the myosin thick filament. The decline in contractile protein explains the decrease in force per cross-sectional area, whereas the thin-filament loss may explain the observed postflight increase in the maximal velocity of shortening in the type I and IIa fiber types. Importantly, the microgravity-induced decline in peak power is partially offset by the increased fiber velocity. Muscle velocity is further increased by the microgravity-induced expression of fast-type myosin isozymes in slow fibers (hybrid I/II fibers) and by the increased expression of fast type II fiber types. SF increases the susceptibility of skeletal muscle to damage, with the actual damage elicited during postflight reloading. Evidence in rats indicates that SF increases fatigability and reduces the capacity for fat oxidation in skeletal muscles. Future studies will be required to establish the cellular and molecular mechanisms of the SF-induced muscle atrophy and functional loss and to develop effective exercise countermeasures.
Article
We examined the effects of a glucocorticoid, corticosterone, on calpain activity, connectin content and protein breakdown in rat muscle. The results indicated that calpain activity was increased by corticosterone and thus breakdown of connectin was stimulated followed by increased breakdown of skeletal muscle protein.
Article
Skeletal muscle adapts to decreases in activity and load by undergoing atrophy. To identify candidate molecular mediators of muscle atrophy, we performed transcript profiling. Although many genes were up-regulated in a single rat model of atrophy, only a small subset was universal in all atrophy models. Two of these genes encode ubiquitin ligases: Muscle RING Finger 1 (MuRF1), and a gene we designate Muscle Atrophy F-box(MAFbx), the latter being a member of the SCF family of E3 ubiquitin ligases. Overexpression of MAFbx in myotubes produced atrophy, whereas mice deficient in either MAFbx orMuRF1 were found to be resistant to atrophy. These proteins are potential drug targets for the treatment of muscle atrophy.
Article
Cancer-related cachexia is caused by a diverse combination of accelerated protein breakdown and slowed protein synthesis. The hypothesis proposed in this study is that supplementation of specific nutrients known to positively support protein synthesis and reduce protein breakdown will reverse the cachexia process in advanced cancer patients. Patients with solid tumors who had demonstrated a weight loss of at least 5% were considered for the study. Patients were randomly assigned in a double-blind fashion to either an isonitrogenous control mixture of nonessential amino acids or an experimental treatment containing beta-hydroxy-beta-methylbutyrate (3 g/d), L-arginine (14 g/d), and L-glutamine (14 g/d [HMB/Arg/Gln]). The primary outcomes measured were the change in body mass and fat-free mass (FFM), which were assessed at 0, 4, 8, 12, 16, 20, and 24 weeks. Thirty-two patients (14 control, 18 HMB/Arg/Gln) were evaluated at the 4-week visit. The patients supplemented with HMB/Arg/Gln gained 0.95 +/- 0.66 kg of body mass in 4 weeks, whereas control subjects lost 0.26 +/- 0.78 kg during the same time period. This gain was the result of a significant increase in FFM in the HMB/Arg/Gln-supplemented group (1.12 +/- 0.68 kg), whereas the subjects supplemented with the control lost 1.34 +/- 0.78 kg of FFM (P = 0.02). The response to 24-weeks of supplementation was evaluated by an intent-to-treat statistical analysis. The effect of HMB/Arg/Gln on FFM increase was maintained over the 24 weeks (1.60 +/- 0.98 kg; quadratic contrast over time, P <0.05). There was no negative effect of treatment on the incidence of adverse effects or quality of life measures. The mixture of HMB/Arg/Gln was effective in increasing FFM of advanced (stage IV) cancer. The exact reasons for this improvement will require further investigation, but could be attributed to the observed effects of HMB on slowing rates of protein breakdown, with improvements in protein synthesis observed with arginine and glutamine.
Article
The target of rapamycin (TOR) proteins in Saccharomyces cerevisiae, TOR1 and TOR2, redundantly regulate growth in a rapamycin-sensitive manner. TOR2 additionally regulates polarization of the actin cytoskeleton in a rapamycin-insensitive manner. We describe two functionally distinct TOR complexes. TOR Complex 1 (TORC1) contains TOR1 or TOR2, KOG1 (YHR186c), and LST8. TORC2 contains TOR2, AVO1 (YOL078w), AVO2 (YMR068w), AVO3 (YER093c), and LST8. FKBP-rapamycin binds TORC1, and TORC1 disruption mimics rapamycin treatment, suggesting that TORC1 mediates the rapamycin-sensitive, TOR-shared pathway. FKBP-rapamycin fails to bind TORC2, and TORC2 disruption causes an actin defect, suggesting that TORC2 mediates the rapamycin-insensitive, TOR2-unique pathway. Thus, the distinct TOR complexes account for the diversity, specificity, and selective rapamycin inhibition of TOR signaling. TORC1 and possibly TORC2 are conserved from yeast to man.
Article
Endotoxin (i.e., lipopolysaccharide, LPS) impairs skeletal muscle protein synthesis. Although this impairment is not acutely associated with a decreased plasma concentration of total amino acids, LPS may blunt the anabolic response to amino acids. To examine this hypothesis, rats were injected intraperitoneally with LPS or saline (Sal) and 4 h thereafter were orally administered either leucine (Leu) or Sal. The gastrocnemius was removed 20 min later to assess signaling components important in the translational control of protein synthesis. In the Sal-Leu group phosphorylation of 4E-BP1 in muscle was markedly increased, compared to values from time-matched saline-treated control rats. This change was associated with a redistribution of eukaryotic initiation factor (eIF) 4E from the inactive eIF4E x 4E-BP1 complex to the active eIF4E x eIF4G complex. In LPS-treated rats, the Leu-induced phosphorylation of 4E-BP1 and changes in eIF4E distribution were partially or completely abrogated. LPS also antagonized the Leu-induced increase in phosphorylation of S6K1, ribosomal protein S6 and mTOR. Neither LPS nor leu altered the total amount or phosphorylation of TSC2 in muscle. The ability of LPS to blunt the anabolic effects of Leu could not be attributed to differences in the plasma concentrations of insulin or Leu between groups. Furthermore, the replacement of plasma insulin-like growth factor (IGF)-I in LPS-treated rats to basal levels also did not ameliorate the defect in leucine-induced phosphorylation of S6K1 or S6, although it did reverse the LPS-induced decrease in the constitutive phosphorylation of mTOR, S6 and 4E-BP1. Pretreatment with the glucocorticoid receptor antagonist RU486 was unable to prevent the LPS-induced leucine resistance. In contrast, to the abovementioned results with leucine, LPS did not prevent the ability of pharmacological levels of IGF-I to phosphorylate 4E-BP1, S6K1, mTOR or alter the availability of eIF4E. Hence, LPS working via a glucocorticoid-independent mechanism produces a leucine resistance in skeletal muscle that might be expected to impair the ability of this amino acid to stimulate translation initiation and protein synthesis.
Article
Loss of skeletal muscle is an important determinant of survival in patients with cancer-induced weight loss. The effect of the leucine metabolite beta-hydroxy-beta-methylbutyrate (HMB) on the reduction of body weight loss and protein degradation in the MAC16 model of cancer-induced weight loss has been compared with that of eicosapentaenoic acid (EPA), a recognized inhibitor of protein degradation. HMB was found to attenuate the development of weight loss at a dose greater than 0.125 g/kg accompanied by a small reduction in tumor growth rate. When EPA was used at a suboptimal dose level (0.6 g/kg) the combination with HMB seemed to enhance the anticachectic effect. Both treatments caused an increase in the wet weight of soleus muscle and a reduction in protein degradation, although there did not seem to be a synergistic effect of the combination. Proteasome activity, determined by the "chymotrypsin-like" enzyme activity, was attenuated by both HMB and EPA. Protein expression of the 20S alpha or beta subunits was reduced by at least 50%, as were the ATPase subunits MSS1 and p42 of the 19S proteasome regulatory subunit. This was accompanied by a reduction in the expression of E2(14k) ubiquitin-conjugating enzyme. The combination of EPA and HMB was at least as effective or more effective than either treatment alone. Attenuation of proteasome expression was reflected as a reduction in protein degradation in gastrocnemius muscle of cachectic mice treated with HMB. In addition, HMB produced a significant stimulation of protein synthesis in skeletal muscle. These results suggest that HMB preserves lean body mass and attenuates protein degradation through down-regulation of the increased expression of key regulatory components of the ubiquitin-proteasome proteolytic pathway, together with stimulation of protein synthesis.
Article
In animals, cells are dependent on extracellular signals to prevent apoptosis. However, using growth factor-dependent cells from Bax/Bak-deficient mice, we demonstrate that apoptosis is not essential to limit cell autonomous survival. Following growth factor withdrawal, Bax-/-Bak-/- cells activate autophagy, undergo progressive atrophy, and ultimately succumb to death. These effects result from loss of the ability to take up sufficient nutrients to maintain cellular bioenergetics. Despite abundant extracellular nutrients, growth factor-deprived cells maintain ATP production from catabolism of intracellular substrates through autophagy. Autophagy is essential for maintaining cell survival following growth factor withdrawal and can sustain viability for several weeks. During this time, cells respond to growth factor readdition by rapid restoration of the ability to take up and metabolize glucose and by subsequent recovery of their original size and proliferative potential. Thus, growth factor signal transduction is required to direct the utilization of sufficient exogenous nutrients to maintain cell viability.
Article
A variety of conditions lead to skeletal muscle atrophy including muscle inactivity or disuse, multiple disease states (i.e., cachexia), fasting, and age-associated atrophy (sarcopenia). Given the impact on mobility in the latter conditions, inactivity could contribute in a secondary manner to muscle atrophy. Because different events initiate atrophy in these different conditions, it seems that the regulation of protein loss may be unique in each case. In fact differences exist between the regulation of the various atrophy conditions, especially sarcopenia, as evidenced in part by comparisons of transcriptional profiles as well as by the unique triggering molecules found in each case. By contrast, recent studies have shown that many of the intracellular signaling molecules and target genes are similar, particularly among the atrophies related to inactivity and cachexia. This review focuses on the most recent findings related to intracellular signaling during muscle atrophy. Key findings are discussed that relate to signaling involving muscle ubiquitin ligases, the IGF/PI3K/Akt pathway, FOXO activity, caspase-3 activity, and NF-kappaB signaling, and an attempt is made to construct a unifying picture of how these data can be connected to better understand atrophy. Once more detailed cellular mechanisms of the atrophy process are understood, more specific interventions can be designed for the attenuation of protein loss.
Article
Malnutrition is a common problem among patients with cancer, affecting up to 85% of patients with certain cancers (e.g. pancreas). In severe cases, malnutrition can progress to cachexia, a specific form of malnutrition characterised by loss of lean body mass, muscle wasting, and impaired immune, physical and mental function. Cancer cachexia is also associated with poor response to therapy, increased susceptibility to treatment-related adverse events, as well as poor outcome and quality of life. Cancer cachexia is a complex, multifactorial syndrome, which is thought to result from the actions of both host- and tumour-derived factors, including cytokines involved in a systemic inflammatory response to the tumour. Early intervention with nutritional supplementation has been shown to halt malnutrition, and may improve outcome in some patients. However, increasing nutritional intake is insufficient to prevent the development of cachexia, reflecting the complex pathogenesis of this condition. Nutritional supplements containing anti-inflammatory agents, for example the polyunsaturated fatty acid (PUFA) eicosapentanoic acid (EPA), have been shown to be more beneficial to malnourished patients than nutritional supplementation alone. EPA has been shown to interfere with multiple mechanisms implicated in the pathogenesis of cancer cachexia, and in clinical studies, has been associated with reversal of cachexia and improved survival.
Article
The goal of this investigation was to test specific exercise and nutrition countermeasures to lower limb skeletal muscle volume and strength losses during 60 days of simulated weightlessness (6 degrees head-down-tilt bed rest). Twenty-four women underwent bed rest only (BR, n = 8), bed rest and a concurrent exercise training countermeasure (thigh and calf resistance training and aerobic treadmill training; BRE, n = 8), or bed rest and a nutrition countermeasure (a leucine-enriched high protein diet; BRN, n = 8). Thigh (quadriceps femoris) muscle volume was decreased (P < 0.05) in BR (-21 +/- 1%) and BRN (-24 +/- 2%), with BRN losing more (P < 0.05) than BR. BRE maintained (P > 0.05) thigh muscle volume. Calf (triceps surae) muscle volume was decreased (P < 0.05) to a similar extent (P > 0.05) in BR (-29 +/- 1%) and BRN (-28 +/- 1%), and this decrease was attenuated (P < 0.05) in BRE (-8 +/- 2%). BR and BRN experienced large (P < 0.05) and similar (P > 0.05) decreases in isometric and dynamic (concentric force, eccentric force, power and work) muscle strength for supine squat (-19 to -33%) and calf press (-26 to -46%). BRE maintained (P > 0.05) or increased (P < 0.05) all measures of muscle strength. The nutrition countermeasure was not effective in offsetting lower limb muscle volume or strength loss, and actually promoted thigh muscle volume loss. The concurrent aerobic and resistance exercise protocol was effective at preventing thigh muscle volume loss, and thigh and calf muscle strength loss. While the exercise protocol offset approximately 75% of the calf muscle volume loss, modification of this regimen is needed.
Article
Excess levels of circulating amino acids (AAs) play a causal role in specific human pathologies, including obesity and type 2 diabetes. Moreover, obesity and diabetes are contributing factors in the development of cancer, with recent studies suggesting that this link is mediated in part by AA activation of mammalian target of rapamycin (mTOR) Complex 1. AAs appear to mediate this response through class III phosphatidylinositol 3-kinase (PI3K), or human vacuolar protein sorting 34 (hVps34), rather than through the canonical class I PI3K pathway used by growth factors and hormones. Here we show that AAs induce a rise in intracellular Ca(2+) ([Ca(2+)](i)), which triggers mTOR Complex 1 and hVps34 activation. We demonstrate that the rise in [Ca(2+)](i) increases the direct binding of Ca(2+)/calmodulin (CaM) to an evolutionarily conserved motif in hVps34 that is required for lipid kinase activity and increased mTOR Complex 1 signaling. These findings have important implications regarding the basic signaling mechanisms linking metabolic disorders with cancer progression.
Article
Muscle wasting in sepsis reflects activation of multiple proteolytic mechanisms, including lyosomal and ubiquitin-proteasome-dependent protein breakdown. Recent studies suggest that activation of the calpain system also plays an important role in sepsis-induced muscle wasting. Perhaps the most important consequence of calpain activation in skeletal muscle during sepsis is disruption of the sarcomere, allowing for the release of myofilaments (including actin and myosin) that are subsequently ubiquitinated and degraded by the 26S proteasome. Other important consequences of calpain activation that may contribute to muscle wasting during sepsis include degradation of certain transcription factors and nuclear cofactors, activation of the 26S proteasome, and inhibition of Akt activity, allowing for downstream activation of Foxo transcription factors and GSK-3beta. The role of calpain activation in sepsis-induced muscle wasting suggests that the calpain system may be a therapeutic target in the prevention and treatment of muscle wasting during sepsis. Furthermore, because calpain activation may also be involved in muscle wasting caused by other conditions, including different muscular dystrophies and cancer, calpain inhibitors may be beneficial not only in the treatment of sepsis-induced muscle wasting but in other conditions causing muscle atrophy as well.