Methods for enhancing exercise performance

Abstract

Disclosed herein are methods for enhancing one or more effects of exercise in a subject by administering a PPARδ agonist (e.g., GW1516) to the subject in combination with an exercise program. Also disclosed are gene expression profiles unique to the combination of agonist-induced PPARδ activation and exercise. Such profiles are useful, at least, in methods for identifying the use of performance-enhancing drugs in exercised subjects (such as, professional or athletes). Direct interactions between PPARδ and exercised-induced kinases (e.g., AMPK or its subunits, AMPK α1 and/or AMPK α2) also are disclosed. Such protein-protein interactions provide new targets for identification of useful compounds.

We claim: 
     
         1 . A method for enhancing an exercise effect in a subject, comprising
 performing by a subject physical activity sufficient to produce an exercise effect; and   administering to the subject an effective amount of a PPARδ agonist, thereby enhancing the exercise effect in the subject.   
     
     
         2 . The method of  claim 1 , wherein the subject is a mammal. 
     
     
         3 . The method of  claim 2 , wherein the subject is a racing mammal. 
     
     
         4 . The method of  claim 3 , wherein the racing mammal is a horse, a dog, or a human. 
     
     
         5 . The method of  claim 1 , wherein the subject is an adult. 
     
     
         6 . The method of  claim 1 , wherein the subject is an exercise-trained subject. 
     
     
         7 . The method of  claim 1 , wherein the PPARδ agonist is GW1516. 
     
     
         8 . The method of  claim 1 , wherein the PPARδ agonist is administered on the same day(s) on which the physical activity is performed. 
     
     
         9 . The method of  claim 1 , wherein the physical activity is an aerobic exercise. 
     
     
         10 . The method of  claim 9 , wherein the aerobic exercise is running. 
     
     
         11 . The method of  claim 9 , wherein the exercise effect is improved running endurance. 
     
     
         12 . The method of  claim 11 , wherein improved running endurance is improved running distance or improved running time or a combination thereof. 
     
     
         13 . The method of  claim 1 , wherein the effective amount is from about 5 mg/kg per day to about 10 mg/kg per day in a single dose or in divided doses. 
     
     
         14 . The method of  claim 1 , wherein administration comprises oral administration, intravenous injection, intramuscular injection, or subcutaneous injection. 
     
     
         15 . The method of  claim 1 , wherein the exercise effect is increased fatty acid oxidation in at least one skeletal muscle of the subject. 
     
     
         16 . The method of  claim 1 , wherein the exercise effect is body fat reduction. 
     
     
         17 . The method of  claim 16 , wherein the body fat is white adipose tissue. 
     
     
         18 . A method for identifying the use of performance-enhancing substances in an exercise-trained subject comprising determining in a biological sample taken from an exercise-trained subject the expression of one or more molecules listed in Tables 2 or 4. 
     
     
         19 . The method of  claim 18 , wherein:
 (i) expression is upregulated in one or more of adipose differentiation related protein; stearoyl-Coenzyme A desaturase 2; acetyl-Coenzyme A acetyltransferase 2; ATP citrate lyase; adiponectin, C1Q and collagen domain containing; diacylglycerol O-acyltransferase 2; lipase, hormone sensitive; monoglyceride lipase; resistin; CD36 antigen; fatty acid binding protein 4, adipocyte; lipoprotein lipase; microsomal glutathione S-transferase 1; GPI-anchored membrane protein 1; dual specificity phosphatase 7; homeodomain interacting protein kinase 3; insulin-like growth factor binding protein 5; protein phosphatase 2 (formerly 2A), regulatory subunit A (PR 65), beta isoform; protein tyrosine phosphatase-like (proline instead of catalytic arginine); member b; CCAAT/enhancer binding protein (C/EBP), alpha; nuclear receptor subfamily 1, group D, member 2(Reverb-b); transferring; archain 1; solute carrier family 1 (neutral amino acid transporter), member 5; RIKEN cDNA 1810073N04 gene; haptoglobin; retinol binding protein 4, plasma; phosphoenolpyruvate carboxykinase 1, cytosolic; cell death-inducing DFFA-like effector c; interferon, alpha-inducible protein 27; carbonic anhydrase 3; cysteine dioxygenase 1, cytosolic; DNA segment, Chr 4, Wayne State University 53, expressed; dynein cytoplasmic 1 intermediate chain 2; Kruppel-like factor 3 (basic); thyroid hormone responsive SPOT14 homolog ( Rattus ); cytochrome P450, family 2, subfamily e, polypeptide 1; complement factor D (adipsin); and/or transketolase; or   (ii) expression is downregulated in one or more of gamma-glutamyl carboxylase; 3-oxoacid CoA transferase 1; solute carrier family 38, member 4; annexin A7; CD55 antigen, RIKEN cDNA 1190002H23 gene; fusion, derived from t(12; 16) malignant liposarcoma (human); lysosomal membrane glycoprotein 2; and/or neighbor of Punc E11; or   (iii) a combination of (i) and (ii).   
     
     
         20 . The method of  claim 18 , wherein determining expression comprises determining protein expression, determining expression of a gene encoding the protein, or a combination thereof. 
     
     
         21 . The method of  claim 20 , comprising determining expression of a gene encoding the protein. 
     
     
         22 . The method of  claim 18 , wherein the biological sample is a skeletal muscle biopsy. 
     
     
         23 . A method of identifying an agent having potential to enhance exercise performance in a subject, comprising:
 providing a first component comprising a PPARδ receptor or an AMPK-binding fragment thereof;   providing a second component comprising an AMP-activated protein kinase (AMPK), AMPKα1, AMPKα2, or a PPARδ-binding fragment of any thereof;   contacting the first component and the second component with at least one test agent under conditions that would permit the first component and the second component to specifically bind to each other in the absence of the at least one test agent; and   determining whether the at least one test agent affects specific binding of the first component and the second component to each other, wherein an effect on specific binding identifies the at least one test agent as an agent having potential to enhance exercise performance in a subject.   
     
     
         24 . The method of  claim 23 , further comprising providing a third component comprising a PPARδ agonist; and contacting the first component, second component, and third component. 
     
     
         25 . The method of  claim 24 , wherein the PPARδ agonist is GW1516.