MX2008006902A - Methods for the treatment of muscle loss - Google Patents

Abstract

The invention provides methods for treating muscle loss in an individual. In one embodiment, the invention includes administering to an individual an effective amount of a branched chain amino acid (BCAA), a BCAA precursor, a BCAA metabolite, a BCAA-rich protein, a protein manipulated to enrich the BCAA content or any combination thereof. The invention further provides nutritional products for such administration, including orally-administrable nutritional products

Description

METHODS FOR THE TREATMENT OF MUSCLE LOSS ENVIRONMENT OF THE INVENTION TECHNICAL FIELD The invention relates generally to the loss of muscle in a mammal, and more particularly to the administration of one or more branched-chain amino acids (BCAA), a precursor of BCAA, a metabolite of BCAA, a protein rich in BCAA, a protein manipulated to enrich the content of BCAA or any combination thereof, in the treatment of muscle loss. The invention also relates to nutritional formulations suitable for that administration.

ENVIRONMENT OF THE TECHNIQUE Amino acids are the monomeric building blocks of proteins, which in turn comprise a wide variety of biological compounds, including enzymes, antibodies, hormones, transport molecules for ions and small molecules, collagen, and muscle tissues. The amino acids are considered hydrophobic or hydrophilic, based on their solubility in water and, more particularly, in the polarities of its side chains. Amino acids that have polar side chains are hydrophilic, while amino acids that have non-polar side chains are hydrophobic. The solubilities of amino acids, in part, determine the structures of proteins. Hydrophilic amino acids tend to form the surfaces of proteins, while hydrophobic amino acids tend to make up the water-insoluble interior portions of proteins.

Of the 20 common amino acids, nine are considered indispensable (essential) in humans, since the body can not synthesize them. Rather, these nine amino acids must be obtained through the diet of the individual. A deficiency of one or more amino acids can cause a negative nitrogen balance. A negative nitrogen balance, for example, is one in which more nitrogen is excreted than the one administered. This condition can lead to the interruption of enzymatic activity and the loss of muscle mass.

A number of muscle wasting conditions have been identified for which treatment with amino acid supplements has proved beneficial. For example, cachexia is a severe condition of shrinkage characterized by marked muscle loss, anorexia, asthenia and anemia. Cachexia is a common representation of numerous diseases, such as cancer, sepsis, chronic heart failure, rheumatoid arthritis, and acquired human immunodeficiency syndrome (AIDS). Other diseases and disorders that deplete the muscles are known, including, for example, sarcopenia, a loss of muscle mass related to age.

Proteolysis induction factor (PIF) It has been found that certain tumors can induce cachexia through the production of a 24 kDa glycoprotein called proteolysis induction factor (PIF). A proposed mechanism of action of PIF is the decrease in protein synthesis; Another proposed mechanism of action of the PIF is an activation of the degradation of the proteins; A third proposed mechanism is a combination of the aforementioned decrease in protein synthesis and the activation of protein degradation. It has been hypothesized that the decreased protein synthesis associated with PIF is the result of the ability of PIF to block the translation process of protein synthesis. Another factor, Angiotensin II (Ang II) has shown effects similar and may be involved in muscle wasting observed in some cases of cachexia.

The original role of PIF in the ubiquitin-proteosome pathway is known. PIF produces an increased release of arachidonic acid, which is then metabolized to prostaglandins and 15-hydroxyeicosatetraenoic acid (15-HETE). It has been shown that 15-HETE produces a significant increase in protein degradation and nuclear binding of the transcription factor NF-? B (a nuclear factor that binds the kappa light chain gene enhancer to immunoglobulin in cells B).

Regulation of protein synthesis via the start of translation It is believed that the role of PIF in the inhibition of protein synthesis is due to the theorized ability of PIF to block translation via RNA-dependent protein kinase activation (PKR) of the downstream factors. The inhibition of protein synthesis by PIF is attenuated by insulin at physiological concentrations and lower. This suggests that PIF can inhibit protein synthesis at the initial stage of translation, since insulin regulates the protein synthesis through the activation of messenger RNA binding steps (mRNA) at the start of translation.

There are two steps at the start of translation that are subject to regulation: (1) the binding of the methionyl transfer initiator RNA (met-tRNA) to the 40s ribosomal subunit; and (2) the binding of the mRNA with the 43s preinitiation complex.

In the first step, met-tRNA binds with the 40s ribosomal subunit as a ternary complex with eukaryotic initiation factor 2 (eIF2) and guanosine triphosphate (GTP). Subsequently, the GTP bound to eIF2 is hydrolyzed to guanosine disphosphate (GDP) and the eIF2 is released from the ribosomal subunit in a GDP-eIF2 complex. The eIF2 must then exchange the GDP for GTP to participate in another round of initiation. This occurs through the action of another eukaryotic initiation factor, eIF2B, which mediates the nucleotide exchange of guanine in eIF2. EIF2B is regulated by the phosphorylation of eIF2 in its alpha subunit, which converts it from a substrate into a competitive inhibitor of eIF2B.

In the second step, the binding of the mRNA with the 43s initiation complex requires a group of proteins collectively called eIF4F, a multiple subunit complex consisting of eIF4A (an RNA helicase), eIF4B (which functions together with eIF4A to unwind the secondary structure in the 5 'untranslated region of the mRNA), the eIF4E (which binds the m7GTP envelope present at the 5' end of the mRNA), and the eIF4G (which functions as a platform for the eIF4E, eIF4A, and mRNA). Collectively, the eIF4F complex serves to recognize, unfold and guide the mRNA to the 43s pre-initiation complex. The availability of eIF4E for the formation of the eIF4F complex appears to be regulated by translational repressor binding protein 1 eIF4E (4E-BP1). 4EBP1 competes with eIF4G to bind to eIF4E and is able to sequester eIF4E within an inactive complex. Binding of 4E-BP1 is regulated through phosphorylation by the mammalian kinase target of rapamycin (mTOR), when increased phosphorylation causes a decrease in the affinity of 4E-BP1 for eIF4E.

It is believed that mTOR is activated by phosphorylation and inhibition of the 1-TSC2 complex of the tuberous sclerosis complex (TSC) via signaling to through the phosphatidylinositol 3 kinase (PI3K) / serine / threonine kinase pathway (PI3K / AKT pathway). MTOR also phosphorylates the p70S6 kinase, which phosphorylates ribosomal protein S6, which is believed to improve the translation of mRNA with a flow of pyrimidine residues adjacent to the 5 'shell structure. The proteins encoded by this mRNA include ribosomal proteins, translational elongation factors, and poly-A binding proteins.

Anabolic factors involved in the initiation of translation Many studies have shown that anabolic factors, such as insulin, insulin-like growth factors (IGF's) and amino acids, increase protein synthesis and cause muscle hypertrophy. Branched-chain amino acids (BCAA's), particularly leucine, can initiate signal transduction pathways that modulate the initiation of translation. These pathways often include mTOR. Other studies have shown that the mitogenic stimulus, such as insulin and BCAA's, point via eIF2. As such, starvation of the amino acid results in increased phosphorylation of eIF2-a and a decrease in protein synthesis.

Signaling pathways involved in the synthesis and degradation of the protein As mentioned above, it is known that PIF induces the degradation of the protein via the NF-? B pathway. Therefore, it is plausible that the inhibition of protein synthesis by PIF occurs through a common point of initiation of signaling, which then diverges into two separate pathways, one that promotes protein degradation via NF -? B, and the other one that inhibits the synthesis of proteins through mTOR and / or eIF2.

AKT is a serine / threonine kinase, also known as protein kinase B (PKB). Activation of AKT occurs through the direct binding of the lipid products of PI3K inositol to its homology domain of plequestrin. PI3K-dependent activation of AKT also occurs through phosphorylation mediated by the phosphoinositide-dependent kinase (PDK1) of threonine 308, which leads to the autophosphorylation of serine 473. Although it was initially thought to operate as the components of Different signaling pathways, several studies have shown that the signaling pathways of NF-KB and AKT converge. Studies have shown that AKT signaling inhibits apoptosis in a variety of cell types in vi tro, mediated by their ability to phosphorylate the regulatory components of apoptosis, including IκB, the kinase involved in the activation of NF-βB. Therefore, the activation of AKT stimulates the activation of NF-? B. Although this would place AKT upstream of NF-? B activation in the sequence of signaling events, one study reports that AKT may be a downstream target of NF-? B. Above all, this suggests that AKT is involved in the catabolic pathway. Other data, however, suggest that AKT is also involved in anabolic processes through the activation of mTOR and the consequent phosphorylation of p70S6 and 4E-BP1 kinase, leading to an increase in protein synthesis.

PKR is a serine / threonine protein-dependent RNA kinase induced by interferon, responsible for the control of an antiviral defense pathway. PKR can be induced by forms of cellular stress other than interferon. Some evidence suggests that the tumor necrosis factor (TNF) -alpha also acts through PKR. Interestingly, both interferon and TNF-alpha have been implicated as causative factors of cachexia states. Following the interaction with the activation stimuli (eg, insulin, IGF, BCAA's), it has been reported that PKR forms homodimers and autophosphorylate. As a result, PKR is able to catalyze the phosphorylation of the target substrates, the best characterization being the phosphorylation of Serine 51 in the eIF2-a subunit. Then eIF2 sequesters eIF2B, a limiting component of the translation rate, resulting in the inhibition of protein synthesis. Recent studies suggest that PKR is physically associated with the I? K complex and stimulates the NF-? B-inducing kinase (NIK) while the phosphorylating I? K results in its subsequent degradation. Some studies suggest that NF-? B is activated by PKR by a mechanism independent of its kinase activity eIF2, while other studies indicate that phosphorylation of eIF2- is required for the activation of NF-? B.

The PKR-like ER resident kinase (PERK) is another kinase that phosphorylates eIF2-a and activates NF-? B. However, it is unlikely that the PIF will act through this path, since the PERK causes the release of I? K from the NF-? B, but not its degradation. In addition, it has been shown that PIF causes the degradation of I? K during the activation of NF-? B.

Known treatments for muscle loss Treatment of conditions such as cachexia often includes nutritional supplementation and in particular amino acid supplementation, in an attempt to increase protein synthesis. The three BCAA's are valine, leucine and isoleucine. Previously, leucine has been shown to function not only as a protein building block, but also as an inducer of signal transduction pathways that modulate the initiation of translation. Our new recent research suggests that the three BCAAs possess the ability to reduce protein degradation and comparably improve the translation of the protein.

Cachexia is just one of the conditions, disorders and diseases for which amino acid supplementation has proved beneficial. Amino acid supplementation has also been used to treat diabetes, hypertension, high serum cholesterol and triglycerides, Parkinson's disease, insomnia, alcohol and drug addiction, pain, insomnia and hypoglycemia. In particular, supplementation with BCAA's has been used to treat liver disorders, including compromised liver function, including cirrhosis, gallbladder disorders, chorea and dyskinesia, and kidney disorders, including uremia. Supplementation with BCAA has also proven to be successful in the treatment of patients undergoing hemodialysis, resulting in improvements in health and mood in general.

To date, the treatment of muscle loss, including treatments involving nutritional supplementation with amino acids, has focused on the promotion of muscle anabolism. For example, US Patent Application Publication No. 2004/0122097 to Verlaan et al., Discloses nutritional supplements containing both leucine and protein to promote the generation of muscle tissue. Leucine precursors, such as pyruvate, and metabolites, such as β-hydroxy-β-methylbutyrate and α-ketoisocaproate, exhibit properties similar to those of leucine. It is noted that ß-hydroxy-ß-methylbutyrate is not produced by humans in any chemically relevant quantity, and therefore must be supplemented.

Others have shown that insulin, an anabolic hormone, is capable of promoting protein synthesis when administered in large doses. For the Therefore, the approaches of the known treatments, although they provide some benefit to individuals suffering from muscle loss, through the increased generation of muscle tissue, do not affect the muscle loss itself. That is, the methods known to treat muscle loss are aimed at increasing muscle anabolism, rather than decreasing muscle catabolism.

The amino acids that comprise skeletal muscle are in a constant state of flux in which the new amino acids, whether they come from administration by enteral or parenteral routes, or are recirculated, are deposited as protein and the current proteins are degraded. Then, the loss of muscle mass can be the result of many factors, including the decreased rate of protein synthesis with normal degradation, increased degradation with normal synthesis or an exacerbation of both reduced synthesis and increased degradation. As a result, therapies whose goal is to increase synthesis only address half of the problem in the disease (s) of muscle wasting.

Accordingly, there is a need in the art for a method to treat muscle loss, which decrease muscle catabolism and, optionally, increase muscle anabolism.

BRIEF DESCRIPTION OF THE INVENTION The invention provides methods for treating muscle loss in an individual. In one embodiment, the invention includes administering to an individual an effective amount of a branched chain amino acid (BCAA), a precursor of BCAA, a metabolite of BCAA, a protein rich in BCAA, a protein engineered to enrich the BCAA content. , or any combination thereof. The invention also provides nutritional products for this administration, including orally administrable nutritional products.

In a first aspect, the invention provides a method for treating muscle loss in an individual, the method comprising: administering to the individual an effective amount of at least one of: a branched chain amino acid (BCAA), a precursor of BCAA, a metabolite of BCAA, a protein rich in BCAA, a protein manipulated to enrich the content of BCAA, where at least one of the BCAA, the BCAA precursor, the BCAA metabolite, the BCAA-rich protein and the manipulated protein to enrich the content of BCAA, it antagonizes protein catabolism.

In a second aspect, the invention provides an orally administrable nutritional product comprising at least one of the following: a branched chain amino acid (BCAA), a precursor of BCAA, a metabolite of BCAA, a protein rich in BCAA, a manipulated protein to enrich the BCAA content, where at least one of the BCAA, the precursor of BCAA, the BCAA metabolite, the protein rich in BCAA and the protein manipulated to enrich the content of BCAA, antagonizes protein catabolism.

The illustrative aspects of the present invention are designed to solve the problems described herein and other problems that are not discussed, which can be discovered by an experienced technician.

BRIEF DESCRIPTION OF THE DRAWINGS These and other representations of the invention will be more readily understood from the following detailed description of the various aspects of the invention taken in conjunction with Figures 1 to 10.

Attachments showing several representations of the invention, in which: Figure 1 shows a graph of the depression of protein synthesis by the factor inducing proteolysis (PIF) in various concentrations.

Figure 2 shows a graph of the effect of amino acids on the phosphorylation of eIF2- and PIF.

Figure 3 shows a graph of the effect of insulin and insulin-like growth factor-1 (IGF) on phosphorylation of PIF eIF2-a.

Figure 4 shows the structure of an RNA-dependent protein kinase (PKR) inhibitor suitable for use in the present invention.

Figure 5 shows a graph of the effect of the PKR inhibitor of Figure 4 on the proteolytic activity of PIF.

Figure 6 shows a graph of the effect of the PKR inhibitor of Figure 4 when reversing a reduction mediated by PIF in protein synthesis.

Figure 7 shows a graph of the effect of the PKR inhibitor of Figure 4 on the proteolytic activity of Angiotensin II.

Figure 8 shows a graph of the effect of the PKR inhibitor of Figure 4 in reversing a reduction of protein synthesis mediated by Angiotensim II.

Figure 9 shows an alternative mechanism of protein degradation caused by proteolysis inducing factor (PIF) and inhibited by branched chain amino acids, insulin and IGF-1.

Figure 10 shows another alternative mechanism of protein degradation caused by the proteolysis induction factor (PIF) through the activation of PKR and eIF2a which is inhibited by branched chain amino acids, insulin and IGF-1.

It is emphasized that Figures 1 to 10 of the invention are not to scale. It is intended that these figures illustrate only the typical aspects of the invention, and therefore should not be considered as limiting the competence of the invention.

DETAILED DESCRIPTION As indicated above, the invention provides methods and related products for the treatment of muscle loss in an individual. More specifically, the methods and products of the invention reduce muscle catabolism, particularly muscle catabolism mediated by the proteolysis induction factor (PIF).

As used herein, the terms "treatment" and "treating" both refer to prophylactic or preventive treatment and to curative or disease-modifying treatment, including the treatment of patients at risk of contracting a disease or suspected of having contracted a disease, as well as patients who are ill or who have been diagnosed as suffering from a disease or medical condition. The terms "treatment" and "treating" also refer to the preservation and / or promotion of health in an individual who does not suffer from a disease, but who may be susceptible to the development of an unhealthy condition, such as nitrogen imbalance. or muscle loss. Consequently, an "effective amount" is an amount that treats a disease or medical condition in an individual or, more generally, provides the individual with a nutritional, physiological or medical benefit. A treatment may be related to the patient or the doctor. In addition, although the terms "individual" and "patient" are often used herein to refer to a human, the invention is not limited thereto. Accordingly, the terms "individual" and "patient" refer to any mammal that suffers from, or at risk of, a medical condition such as muscle loss.

Experimental data To determine the efficacy of branched chain amino acids (BCAA's) and other agents in the reduction of muscle catabolism, murine C2C12 myotubes were exposed to PIF or Angiotensin II in combination with amino acids (including BCAA's), insulin, factor 1 of insulin-like growth (IGF-1) and inhibitor of PKR. The PIF was extracted and purified from MAC16 tumors as described by Smith et al., In Effect of a cancer cachectic factor on protein syn thesis / degradation in murine C2C12 myoblasts: modulation by eicosapen taenoic acid, Cancer Research, 59: 5507- 13 (1999), which is incorporated herein by reference, Degradation of the protein was determined using the method described by hitehouse et al., Increased expression of the ubiqui tin-proteasome pa thway in murine myotubes by proteolysis-inducing factor (PIF) is associated with the activation of the transcription factor NF-? B, British Journal of Cancer, 89: 116-22 (2003), which is also incorporated here as a reference.

Figure 1 shows a graph of PIF protein synthesis depression at increasing concentrations, measured in counts per minute (CPM) as a percentage of a control that does not contain PIF. A significant reduction in protein synthesis is noted, with a maximum depression of protein synthesis occurring at a PIF concentration of 4.2 nM. The measured proteolytic activity of PIF can be described more specifically as the ubiquitin-like degradation activity.

Figure 2 shows a graph of western blot densitometric analysis of phosphorylated eIF2-a in C2C? 2 myotubes incubated with PIF, leucine, isoleucine, valine, methionine and arginine, either alone or in combination with PIF. The control sample was incubated only in phosphate buffered saline (PBS). As can be seen in Figure 2, PIF significantly increases the phosphorylation of eIF2-a, in comparison with control. Each of the amino acids reduced phosphorylation of eIF2-a in the presence of PIF, compared to PIF alone. However, BCAA's (ie, leucine, isoleucine, and valine) reduced that phosphorylation to near the control level or lower, while the phosphorylation levels induced by methionine and arginine were greater than that of the control. Surprisingly, unlike the known treatment methods that are directed towards increasing protein synthesis, and where leucine shows greater efficacy than the other BCAA's, these data show that all BCAA's are approximately equally effective in reducing phosphorylation of eIF2-a induced by PIF. In fact, the phosphorylation levels resulting from the incubation in isoleucine and in valine were not different from those observed with the incubation in leucine.

Figure 3 shows the results of similar experiments involving the incubation of insulin and IGF-1, alone and in combination with PIF. Both insulin and IGF-1 significantly reduced the phosphorylation of eIF2-a in the presence of PIF, compared to PIF alone. Therefore, the ability of BCAAs to decrease the degradation of the protein mediated by PIF can be supplemented or improved upon the addition of insulin and / or IGF-1 or by treatments that increase the level of insulin and / or IGF-1.

Figure 4 shows the structure of the PKR inhibitor useful both in the decrease in protein induced by PIF and in the increase in protein synthesis that was used as a positive control of PKR inhibition. Figures 5-8 show the results of the experiments involving the incubation of the PKR inhibitor in combination with either PIF or Angiotensin II. In Figure 5, it can be seen that, while the PIF increased protein degradation up to 87% when incubated alone, the addition of the PKR inhibitor reversed the levels of protein degradation back up to those of the control. Similarly, in Figure 6 it can be seen that, while PIF reduced protein synthesis to about 25% when incubated alone, the addition of the PKR inhibitor reversed the synthesis levels of the protein back to near the of control.

Figures 7 and 8 show similar results with the incubation of the PKR inhibitor with Angiotensin II.

In Figure 7, Angiotensin increased the degradation of the protein to about 51%, compared to the control. The addition of the PKR inhibitor reversed this tendency, maintaining protein degradation levels to approximately those of the control. Similarly, in Figure 8, Angiotensin II reduced protein synthesis to about 40% compared to control, while addition of the PKR inhibitor maintained protein synthesis levels close to those of the control .

The PKR inhibitor attenuated the actions of PIF and Angiotensin II in both the protein degradation and protein synthesis. This suggests that both PIF and Angiotensin II mediate their effects through similar mechanisms and through a common mediator, which seems to involve PKR. More specifically, these results suggest that PIF activates PKR, which in turn causes phosphorylation of eIF2-a, inhibiting the binding of the methionyl-tRNA initiator (met-tRNA) with the 40s ribosomal subunit. The BCAA's, insulin, and IGF-1, attenuated the phosphorylation of eIF2-a caused by PIF, also supporting the hypothesis that PIF up-regulates the phosphorylation of eIF2-a to inhibit protein synthesis. Since PKR can inhibit protein synthesis and activate NF-? B, which leads to protein degradation, PKR appears to be an early component in the PIF signaling pathway.

There is also evidence that PKR is involved in the regulation of phosphorylation of 4E-BP1. Therefore, if PIF points through PKR, it seems that this can also reduce protein synthesis through PKR-mediated activation of the serine / threonine phosphatase PP2A, which can cause dephosphorylation of 4E-BP1 , which in turn hijacks the eIF4E in an inactive complex, avoiding the formation of the 43s pre-initiation complex.

Figure 9 shows an alternative mechanism. Both the proteolysis-inducing factor (PIF) and Angiotensin II (Ang II) decrease protein synthesis by 40%, and the concentrations of both agents that are most effective in the depression of protein synthesis are the same as those that are effective to the maximum in the induction of the degradation of the protein. The results suggest that both insulin and IGF-1, at least partially, attenuate protein degradation induced by PIF through the inhibition of phosphorylation of PKR and / or eIF2a. The mechanism of activation by PIF and Ang II can be through PACT (interferon-induced protein kinase protein activator), a cellular protein activator of PKR, although PIF It is also a polyanionic molecule, and therefore can be activated directly. However, the phosphorylation of eIF2a and Ang II seems to occur through PKR, since a PKR inhibitor attenuated the inhibitory effect of both agents in protein synthesis. The effect of both PIF and Ang II on the translation of the protein appears to arise from increased phosphorylation of eIF2a.

Inhibition of protein synthesis in apoptosis by tumor necrosis factor-a (TNF-a) is also associated with increased phosphorylation of eIF2a. Additional support for the role of eIF2a phosphorylation in the inhibition of protein synthesis by PIF and Ang II, is provided by the observation that both of insulin and IGF-1, which were effective in suppressing inhibition of The synthesis of proteins, completely attenuated the induction of eIF2a phosphorylation. The data gathered suggest that BCAAs also work through the same mechanism to inhibit the degradation pathway initiated by the PIF. This study provides the first evidence of a relationship between the depression of protein synthesis in skeletal muscle by PIF (and Ang II), through the activation of phosphorylation of PKR and eIF2a, and increased degradation of myosin protein myofibrillar, through the activation of NF-? B that results in increased expression and activity of the proteolytic ubiquitin-proteasome pathway. This suggests that agents that focus on PKR (for example, BCAA's) may be effective in the treatment of muscle atrophy in cancer cachexia.

Figure 10 shows another alternative mechanism. As previously stated, both the proteolysis-inducing factor (PIF) and Angiotensin II (Ang II) increase the degradation of the protein through the phosphorylation of PKR and / or eIF2a. The NF-? B can be activated by the PIF or by a mediator downstream of the PIF (PKR and / or eIF2a) that occurs through the release of NF-? B. In this alternative mechanism, NF-? B is not part of the same phosphorylation cascade despite having the same goal to promote the ubiquitin labeling of proteins that will be degraded.

Together, the above data supports a number of new aspects of the present invention. First, BCAAs can be employed to treat muscle loss in an individual by antagonizing the catabolism of the protein mediated by PIF and / or Angiotensin II through the inhibition of PKR and / or eIF2a activation. In Second, each of the BCAAs is equally effective in that antagonism. Third, the co-administration of insulin, IGF-1 and / or a PKR inhibitor, or the use of treatments to increase the level of either or both of insulin and IGF-1, may increase the efficacy of treatments with BCAA by also antagonizing the catabolism of the protein, by improving protein synthesis, or both.

The nutritional products according to the invention may therefore include BCAA's, alone or in combination with insulin, IGF-1 and / or a PKR inhibitor. BCAA's can be administered in their free forms, as dipeptides, as tripeptides, as polypeptides, as a BCAA-rich protein and / or as a manipulated protein to enrich the BCAA content. The dipeptides, the tripeptides and the polypeptides may include two or more BCAA's. When non-BCAA's are included in a dipeptide, tripeptide or polypeptide, the preferred amino acids include alanine and glycine, but non-BCAA's can be any of the dispensable or indispensable amino acids (essential or non-essential). For example, preferred dipeptides include, but are not limited to, alanyl-leucine, alanyl-isoleucine, alanyl-valine, glycyl-leucine, glycyl-isoleucine and glycyl-valine.

The nutritional products according to the invention can similarly include precursors and / or BCAA's metabolites, particularly precursors and / or leucine metabolites, in addition to or in place of the BCAA's. These products may also include any number of additional ingredients, including, for example, a protein, a fiber, a fatty acid, a vitamin, a mineral, a sugar, a carbohydrate, or flavoring agent, a medicament, and a therapeutic agent. .

The nutritional products of the present invention can be administered orally, through a feeding tube, or parenterally. These products can be used in the treatment of an individual suffering from any number of diseases, disorders or conaitions of muscular wastage, or of any disease, disorder or condition with which muscle loss is associated, including, for example, cachexia, cancer , tumor-induced weight loss, sepsis, chronic heart failure, rheumatoid arthritis, acquired immunodeficiency syndrome (AIDS), sarcopenia, diabetes, hypertension, high serum cholesterol levels, high triglyceride levels, Parkmson's disease, insomnia, addiction to drugs, alcohol addiction, pain, insomnia, hypoglycemia, compromised liver function, including cirrhosis, gallbladder disorders, chorea, dyskinesia, and kidney disorder, including uremia.

The above description of the various aspects of the invention has been presented for the purposes of illustration and description. They are not intended to be exhaustive or to limit the invention to the precise form described, and obviously many modifications and variations are possible. These modifications and variations that may be apparent to a person skilled in the art are intended to be included within the competence of the invention as defined in the appended claims.

Claims (43)

1. CLAIMS 1. Method for treating muscle loss in an individual, the method comprising administering to the individual an effective amount of at least one of: a branched-chain amino acid (BCAA); a precursor of BCAA; a metabolite of BCAA; a protein rich in BCAA; or a manipulated protein to enrich the BCAA content, where at least one of the BCAA, the BCAA precursor, the BCAA metabolite, a protein rich in BCAA, and a protein manipulated to enrich the BCAA content, antagonizes protein catabolism .
2. 2. Method according to claim 1, characterized in that the administration step includes administering a plurality of BCAA's.
3. 3. Method according to claim 1, characterized in that the BCAA is selected from a group consisting of leucine, isoleucine and valine. Four . Method according to claim 1, characterized in that at least one of the BCAA, the precursor of BCAA, the metabolite of BCAA, a protein rich in BCAA or protein manipulated to enrich the BCAA content, promotes protein synthesis. Method according to claim 1, characterized in that the BCAA is administered as at least one of: a dipeptide, a tripeptide, a polypeptide or a peptide enriched in BCAA's. 6. Method according to claim 5, characterized in that the dipeptide includes two branched chain amino acids. Method according to claim 5, characterized in that the dipeptide, the tripeptide or the polypeptide comprises at least one essential or dispensable amino acid, where at least one indispensable amino acid is a BCAA. 8. Method according to claim 5 characterized in that the dipeptide includes one of alanine and glycine. 9. Method according to claim 5, characterized in that the dipeptide is selected from a group consisting of: alanyl-leucine, alanyl-isoleucine, alanii-valine, glycine-Ieucine, glycine-isoieucine, and glycyl-valine. 10. Method according to claim 5, characterized in that the tripeptide includes at least two BCAA 's. 11. Method according to claim 1, characterized in that the BCAA precursor includes pyruvate. 12. Method according to claim 1, characterized in that the metabolite of BCAA is selected from between a group consisting of: β-hydroxy-β-methylbutyrate and β-ketoisocaproate. 13. Method according to claim 1, characterized in that it also comprises administering to the individual at least one of insulin and insulin-like growth factor-1 (IGF-1). 14. Method according to claim 1, characterized in that it also comprises administering to the individual an inhibitor of RNA-dependent protein kinase (PKR). 15. Method according to claim 14, characterized in that the PKR inhibitor has the structure 16. Method according to claim 1, characterized in that it also comprises treating the individual to raise a level of at least one of the following: insulin and IGF-1. Method according to claim 1, characterized in that at least one of the following is administered in an orally administrable nutritional product: the BCAA, the precursor of BCAA, the metabolite of BCAA, the protein rich in BCAA; or the manipulated protein to enrich the content of BCAA. Method according to claim 17, characterized in that the orally administrable nutritional product also includes at least one of the following: a protein, a fiber, a fatty acid, a vitamin, a mineral, a sugar, a carbohydrate, a flavor agent, a medicine and a therapeutic agent. 19. Method according to claim 1, characterized in that at least one of the following is administered via a feeding tube: the BCAA, the precursor of BCAA, the metabolite of BCAA, the protein rich in BCAA; or the manipulated protein to enrich the BCAA content. 20. Method according to claim 1, characterized in that at least one of the following is administered parenterally: the BCAA, the precursor of BCAA, the metabolite of BCAA, and the dipeptide or tripeptide containing at least one BCAA. 21. Method according to claim 1, characterized in that the catabolism of the protein is mediated directly or indirectly by: (a) the proteolysis inducing factor (PIF); (b) Angiotensin II; (c) the PKR; (d) eIF2a; or (e) a combination thereof. 22. Method according to claim 1, characterized in that the individual has at least one of the following: cachexia, cancer, tumor-induced weight loss, sepsis, chronic heart failure, rheumatoid arthritis, acquired immunodeficiency syndrome (AIDS), sarcopenia, diabetes, hypertension, high serum cholesterol levels, high triglyceride levels, Parkinson's, insomnia, drug addiction, alcohol addiction, pain, insomnia, hypoglycemia, compromised liver function, including cirrhosis, gallbladder disorders, chorea, dyskinesia, and kidney disorder, including uremia. 23. A nutritional product comprising at least one of the following: a branched chain amino acid (BCAA); a precursor of BCAA; a metabolite of BCAA; a protein rich in BCAA; or a manipulated protein to enrich the BCAA content, where at least one of the BCAA, the BCAA precursor, the BCAA metabolite, the BCAA-rich protein, and a manipulated protein to enrich the BCAA content, antagonizes protein catabolism . 24. Product according to claim 23, characterized in that it comprises a plurality of BCAA's. 25. Product according to claim 23, characterized in that the BCAA is selected from a group consisting of leucine, isoleucine and valine. 26. Product according to claim 23, characterized in that at least one of the BCAA, the precursor of BCAA, the metabolite of BCAA, the protein rich in BCAA or the protein manipulated to enrich the BCAA content, also promotes protein synthesis. Product according to claim 23, characterized in that the BCAA is administered as at least one of: a dipeptide, a tripeptide, or a polypeptide. 28. Product according to claim 27, characterized in that the dipeptide includes two branched chain amino acids. 29. Product according to claim 27, characterized in that the dipeptide, the tripeptide or the polypeptide comprises at least one essential or dispensable amino acid, wherein at least one indispensable amino acid is a BCAA. 30. Product according to claim 27, characterized in that the dipeptide includes one of alanine and glycine. 31. Product according to claim 27, characterized in that the dipeptide is selected from a group consisting of: alanyl-leucine, alanyl-isoleucine, alanyl-valine, glycyl-leucine, glycyl-isoleucine, and glycyl-valine. 32. Product according to claim 27, characterized in that the tripeptide includes at least two BCAA's. 33. Product according to claim 23, characterized in that the BCAA precursor includes pyruvate. 34. Product according to claim 23, characterized in that the BCAA metabolite is selected from a group consisting of: β-hydroxy-β-methylbutyrate and β-ketoisocaproate. 35. Product according to claim 23, characterized in that it also comprises at least one of insulin and insulin-like growth factor-1 (IGF-1). 36. Product according to claim 23, characterized in that it also comprises an inhibitor of RNA-dependent protein kinase (PKR). 37. Product according to claim 36, characterized in that the PKR inhibitor has the structure: 38. Product according to claim 23, characterized in that it also comprises at least one of the following: a protein, a fiber, a fatty acid, a vitamin, a mineral, a sugar, a carbohydrate, a flavoring agent, a medicine, and a therapeutic agent. 39. Product according to claim 23, characterized in that the catabolism of the protein is mediated directly or indirectly by: (a) the proteolysis inducing factor (PIF); (b) Angiotensin II; (c) the PKR; (d) eIF2a; or (e) a combination thereof. 40. Product according to claim 23, characterized in that the product can be administered orally or via a feeding tube. 41. Product according to claim 23, characterized in that at least one of the following is administered parenterally: the BCAA, the precursor of BCAA, the metabolite of BCAA, and the dipeptide or tripeptide containing at least one BCAA. 42. Administration to an individual who can benefit from an effective amount of at least one of: a branched-chain amino acid (BCAA); a precursor of BCAA; a metabolite of BCAA; a protein rich in BCAA; and a manipulated protein to enrich the BCAA content, where at least one of the BCAA, the BCAA precursor, the BCAA metabolite, the BCAA-rich protein, the protein engineered to enrich the BCAA content, antagonizes protein catabolism . 43. Administration according to claim 42, characterized in that the individual has at least one of the following: cachexia, cancer, tumor-induced weight loss, sepsis, chronic heart failure, arthritis rheumatoid, acquired immunodeficiency syndrome (AIDS), sarcopenia, diabetes, hypertension, high serum cholesterol levels, high triglyceride levels, Parkinson's disease, insomnia, drug addiction, alcohol addiction, pain, insomnia, hypoglycemia, liver function compromised, including cirrhosis, gallbladder disorders, chorea, dyskinesia, and kidney disorder, including uremia. SUMMARY The invention provides methods for treating muscle loss in an individual. In one embodiment, the invention includes administering to an individual an effective amount of a branched chain amino acid (BCAA), a precursor of BCAA, a metabolite of BCAA, a protein rich in BCAA, a protein engineered to enrich the content of BCAA, or any combination thereof. The invention also provides nutritional products for that administration, including orally administrable nutritional products.