Modulation of estrogen receptor-related receptor gamma (err gamma) and uses therefor

Abstract

This application provides methods of increasing vascularization, muscle performance, muscle rehabilitation, and/or mitochondrial activity in subjects in need thereof, by administering a therapeutically effective amount of one or more agents that increases ERRγ activity to the subject. Such agents can include one or more ERRγ agonists. In some examples the method does not require that the subject exercise, and as such, the subject may be sedentary (such as bedridden or in a wheelchair).

1 . A method of increasing mitochondrial activity, comprising:
 administering a therapeutically effective amount of one or more agents that increases ERRγ activity to a mammal needing increased mitochondrial activity; and   not exercising the mammal.   
     
     
         2 . The method of  claim 1 , wherein the method further comprises:
 selecting a mammal in need of increased mitochondrial activity or a mammal at risk for developing a disorder that can benefit from increased mitochondrial activity.   
     
     
         3 . The method of  claim 1 , wherein increased mitochondrial activity is needed in the mammal's muscle, brain or ear. 
     
     
         4 . The method of  claim 1 , wherein the mammal has or is at risk for muscle atrophy, muscle wasting, sarcopenia, hearing loss, mitochondrial encephalomyopathy, lactic acidosis, Leber's hereditary optic neuropathy (LHON), or stroke-like episode syndrome (MELAS). 
     
     
         5 . The method of  claim 1 , wherein the one or more agents that increases ERRγ activity comprises:
 a nucleic acid molecule encoding ERRγ; 
 one or more ERRγ agonists; 
 an ERRγ protein; or 
 combinations thereof. 
 
     
     
         6 . The method of  claim 1 , wherein the ERRγ agonist is: 
       
         
           
           
               
               
           
         
         or combinations thereof. 
       
     
     
         7 . The method of  claim 1 , wherein the one or more agents that increases ERRγ activity is: 
       
         
           
           
               
               
           
         
       
     
     
         8 . The method of  claim 1 , wherein the one or more agents that increases ERRγ activity is: 
       
         
           
           
               
               
           
         
         wherein R is H (DY162), p-CH 3  (DY163), 2-Cl, 3-CF 3  (DY165), p-CF 3  (DY168), p-OCH 3  (DY169), 3-NO 2 , 4CF 3  (DY170), 2,3-O 2 CH 3  (DY174), or m-CH 3  (DY159), 
       
       
         
           
           
               
               
           
         
         wherein X is S and R is 5-CH 3  (DY166), 5-CH 2 CH 3  (DY164), or 5-NO 2  (DY167); 
       
       wherein X is O and R is 4,5-CH 3  (DY173) or CH 2 CH 3  (DY175), or wherein X is CH, and R is 2-Cl, 3-CF 3 , p-CF 3 ; p-OCH 3 , 3-NO 2 , 4-CF 3 ; or 2,3-O 2 CH 3 ; 
       
         
           
           
               
               
           
         
         wherein R is H (DY117) or R is Br (DY172), 
       
       
         
           
           
               
               
           
         
         wherein
 m is 0, 1 or 2; 
 n is 0, 1 or 2; 
 R 1  and R 7  are independently selected from
 1) H; 
 2) Halo; 
 3) OH; 
 4) (C=0) a , O b C 1 -C 4  alkyl, wherein a is 0 or 1 and b is 0 or 1, wherein the alkyl can be substituted by 0, 1 or more substituted groups independently selected from H or C3C6 heterocyclyl; 
 5) (C=0), O b C 3 -C 6  cycloalkyl, wherein a is 0 or 1 and b is 0 or 1; 
 
 R2 is selected from:
 1) H; 
 2) C 1 -C 3  alkyl, wherein the alkyl can be substituted by 0, 1 or more substituted groups independently selected from H or C 3 C 6  heterocyclyl; 
 3) C 3 -C 6  cycloalkyl; 
 
 
       
       
         
           
           
               
               
           
         
       
       or combinations thereof. 
     
     
         9 . The method of  claim 3 , wherein increased mitochondrial activity is needed in the mammal's skeletal muscle, and the mammal has or is at risk for muscle atrophy, sarcopenia, or muscle wasting. 
     
     
         10 . The method of  claim 3 , wherein increased mitochondrial activity is needed in the mammal's cardiac muscle, and the mammal has or is at risk for a heart attack or ischemia in a cardiac muscle. 
     
     
         11 . The method of  claim 1 , wherein the mammal cannot exercise or is sedentary. 
     
     
         12 . The method of  claim 1 , wherein the mammal is a human. 
     
     
         13 . The method of  claim 1 , wherein the administration comprises parenteral, subcutaneous, intraperitoneal, intrapulmonary, or intranasal administration. 
     
     
         14 . A method of increasing mitochondrial activity by at least 25%, comprising:
 administering a therapeutically effective amount of one or more agents that increases ERRγ activity to a mammal needing increased mitochondrial activity; and   not exercising the mammal,   wherein the increase of at least 25% as compared is relative to an amount of mitochondrial activity in the absence of administration of the one or more agents that increases ERRγ activity.