METHODS FOR ENHANCING MUSCLE PERFORMANCE AND TONE

• US 20110112047A1
• Filed: 12/29/2008
• Published: 05/12/2011
• Est. Priority Date: 12/29/2006
• Status: Active Grant

• Current Assignee: Salk Institute for Biological Studies
• Original Assignee: Salk Institute for Biological Studies
• Inventors: Evans, Ronald M., Narkar, Vihang A., Shaw, Reuben J., Yu, Ruth T., Downes, Michael
• Granted Patent: US 9,192,601 B2
• Time in Patent Office: Days
• US Class Current: 514/52
• CPC Class Codes: A61K 31/4178 not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
• CPC Class Codes: A61K 31/426 1,3-Thiazoles
• CPC Class Codes: A61K 31/47 Quinolines; Isoquinolines
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/06 Anabolic agents androgens A61P5/26
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C12Q 1/6876 Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
• CPC Class Codes: C12Q 2600/124 Animal traits, i.e. production traits, including athletic performance or the like
• CPC Class Codes: C12Q 2600/136 Screening for pharmacological compounds
• CPC Class Codes: C12Q 2600/158 Expression markers

Abstract

This disclosure concerns the use of agonists of AMP-activated protein kinase (AMPK) for improving exercise and modifying energy metabolism in a subject. The disclosure also relates to a combination of AMPK and peroxisome proliferator-activated receptor (PPAR) δ agonists for improving exercise performance in a subject, methods for identifying substance-enhanced exercise performance in a subject, and methods for identifying compounds that affect the interaction of PPARδ with exercise-induced kinases.

Claims

1. A method for improving or maintaining muscle tone or mass in a subject having a muscle wasting disease or disorder by administering to the subject an effective amount of a compound comprising an AMP kinase (“

AMPK”

) agonist.

2. The method of claim 1, wherein the AMPK agonist is AICAR.

3. The method of claim 1, further comprising administering an effective amount of a PPARδ

agonist, thereby enhancing an exercise effect in the subject.

4. The use method of claim 1, wherein the subject is a mammal.

5. The method of claim 4, wherein the subject is a racing mammal.

6. The method of claim 5, wherein the racing mammal is a horse, a dog, or a human.

7. The method of claim 4, wherein the subject is an adult.

8. The method of claim 1, wherein the subject is an exercise-trained subject.

9. The method of claim 3, wherein the PPARδ

agonist is GW1516.

10. The method of claim 3, wherein the PPARδ

agonist is administered on the same day(s) on which the AMPK agonist is administered.

11. The method of claim 8, wherein the AMPK agonist is AICAR and the PPARδ

agonist is GW1516.

12. The method of claim 3, further comprising having the subject perform aerobic exercise.

13. The method of claim 3, wherein the exercise effect is improved endurance.

14. The method of claim 13, wherein improved endurance comprises improved running distance or improved running time or a combination thereof.

15. The method of claim 1, wherein an effective amount is from about 0.5 mg/kg per day to about 100 mg/kg per day in a single dose or in divided doses.

16. The method of claim 1, wherein the compound is formulated for oral administration, intravenous injection, intramuscular injection, or subcutaneous injection.

17. The method of claim 3, wherein an exercise effect is increased fatty acid oxidation in at least one skeletal muscle of the subject.

18. The method of claim 3, wherein an exercise effect is body fat reduction.

19. The method of claim 18, wherein the body fat is white adipose tissue.

20. A composition comprising an AMP kinase agonist for use in treating muscle tone, endurance or mass in a subject.

21. The composition of claim 20, wherein the AMPK agonist is AICAR.

22. The composition of claim 20, further comprising an effective amount of a PPARδ

agonist, thereby enhancing an exercise effect in the subject.

23. The composition of claim 20, wherein the subject is a mammal.

24. The composition of claim 23, wherein the subject is a racing mammal.

25. The composition of claim 24, wherein the racing mammal is a horse, a dog, or a human.

26. The composition of claim 23, wherein the subject is an adult.

27. The composition of claim 20, wherein the subject is an exercise-trained subject.

28. The composition of claim 23, wherein the PPARδ

agonist is GW1516.

29. The composition of claim 23, wherein the PPARδ

agonist is administered on the same day(s) on which the AMPK agonist is administered.

30. The composition of claim 28, wherein the AMPK agonist is AICAR and the PPARδ

agonist is GW1516.

31. The composition of claim 23, further comprising having the subject perform aerobic exercise.

32. The composition of claim 23, wherein the exercise effect is improved endurance.

33. The composition of claim 32, wherein improved endurance comprises improved running distance or improved running time or a combination thereof.

34. The composition of claim 20, wherein an effective amount is from about 0.5 mg/kg per day to about 100 mg/kg per day in a single dose or in divided doses.

35. The composition of claim 20, wherein the compound is formulated for oral administration, intravenous injection, intramuscular injection, or subcutaneous injection.

36. The composition of claim 23, wherein an exercise effect is increased fatty acid oxidation in at least one skeletal muscle of the subject.

37. The composition of claim 23, wherein an exercise effect is body fat reduction.

38. The composition of claim 37, wherein the body fat is white adipose tissue.

39. 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.

40. The method of claim 39, 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, ClQ 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 (foraierly 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 I) (adipsin);

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;

1β

) malignant liposarcoma (human);

lysosomal membrane glycoprotein 2;

or neighbor of Punc El 1;

or (iii) a combination of (i) and (ii).

41. The method of claim 39, wherein determining expression comprises determining protein expression, determining expression of a gene encoding the protein, or a combination thereof.

42. The method of claim 41, comprising determining expression of a gene encoding the protein.

43. The method of claim 39, wherein the biological sample is a skeletal muscle biopsy.

70. The method of claim 40, wherein determining expression comprises determining protein expression, determining expression of a gene encoding the protein, or a combination thereof.

71. The method of claim 70, comprising determining expression of a gene encoding the protein.

44. A composition comprising an AMPK agonist and a PPARδ

agonist in a pharmaceutically acceptable carrier.

45. The composition of claim 44, wherein the AMPK agonist is an AICAR, salt, ester, prodrug, precursors or derivative thereof.

46. The composition of claim 44, wherein the PPARδ

agonist is GW1516, salt, ester, prodrug, precursor, or derivative thereof.

47. A method of treating a muscle wasting disease, muscle atrophy or aging comprising administering to a subject a composition comprising an AMPK agonist, wherein the muscle tone or mass is promoted.

48. The method of claim 47, wherein the AMPK agonist is AICAR.

49. The method of claim 47, wherein the composition further comprises a PPARδ

agonist.

72. The method of claim 48, wherein the composition further comprises a PPARδ

agonist.

50. A method of identifying a muscle promoting agent comprising contacting a subject with an agents and measuring the expression of a set of endurance gene signatures comprising the genes in Table 2 or 4 or a subset thereof, wherein the expression of a set of such genes is indicative of a muscle promoting agent.

51. A method for improving or maintaining muscle mass or tone in a subject, comprising administering to the subject an AMP kinase (AMPK) agonist wherein the muscle tone or mass is maintained in a sedentary or immobilized subject or increased in the subject.

52. The method of claim 51, wherein the AMPK agonist is AICAR.

53. The method of claim 51, further comprising administering to the subject an effective amount of a PPARδ

agonist, thereby enhancing an exercise effect in the subject.

54. The method of claim 51, wherein the subject is a mammal.

55. The method of claim 54, wherein the subject is a racing mammal.

56. The method of claim 55, wherein the racing mammal is a horse, a dog, or a human.

57. The method of claim 54, wherein the subject is an adult.

58. The method of claim 51, wherein the subject is an exercise-trained subject.

59. The method of claim 53, wherein the PPARδ

agonist is GW1516.

60. The method of claim 53, wherein the PPARδ

agonist is administered on the same day(s) on which the AMPK agonist is administered.

61. The method of claim 58, wherein the AMPK agonist is AICAR and the PPARδ

agonist is GW1516.

62. The method of claim 53, further comprising having the subject perform aerobic exercise.

63. The method of claim 53, wherein the exercise effect is improved endurance.

64. The method of claim 53, wherein improved endurance is improved running distance or improved running time or a combination thereof.

65. The method of claim 51, wherein an effective amount is from about 0.5 mg/kg per day to about 100 mg/kg per day in a single dose or in divided doses.

66. The method of claim 51, wherein administration comprises oral administration, intravenous injection, intramuscular injection, or subcutaneous injection.

67. The method of claim 53, wherein an exercise effect is increased fatty acid oxidation in at least one skeletal muscle of the subject.

68. The method of claim 53, wherein an exercise effect is body fat reduction.

69. The method of claim 58, wherein the body fat is white adipose tissue.