Agents and methods using thereof for the prevention and treatment of stem cell muscle disorders

Abstract

The present invention relates to agents that induce mitochondrial unfolded protein response (UPR mt ) in muscle stem cells and prevents or reverse process of muscle stem cell senescence. Further, the invention relates to methods and compositions useful in the prevention and/or treatment of muscle stem senescence.

1 . A pharmaceutical composition comprising at least one UPR mt  inducing agent and further comprising an agent useful for the prevention and/or treatment of diseases or disorders associated with MuSCs senescence and/or decreased MuSCs number and/or for promoting muscle tissue growth and/or repair,
 wherein said diseases or disorders are selected from Duchenne's muscular dystrophy (DMD), Becker's muscular dystrophy, Congenital muscular dystrophy, Distal muscular dystrophy, Emery-Dreifuss' muscular dystrophy, Facio-scapulo-humeral muscular dystrophy, Limb-girdle muscular dystrophy, myotonic muscular dystrophy, oculopharyngeal muscular dystrophy, non-mitochondrial myopathies, myotonia, congenital myopathies selected from nemaline myopathy, multi/minicore myopathy and centronuclear myopathy, metabolic myopathies, inflammatory myopathies, muscle stem cell senescence caused by nutritional deficiencies, chronic obstructive pulmonary disease, cachexia of cancer, diseases resulting from clinical treatments with anthracyclines and/or for promoting muscle tissue growth and/or repair after graft, and   wherein said mitochondrial UPR mt  inducing agent selected from nicotinamide riboside (NR), thiamphenicol (TAP) and analogues thereof.   
     
     
         2 . A food supplement comprising at least one agent selected from one UPR mt  inducing agent and further comprising an agent useful for the prevention and/or treatment of diseases or disorders associated with MuSCs senescence and/or decreased MuSCs number and/or for promoting muscle tissue growth and/or repair, wherein said diseases or disorders are selected from Duchenne's muscular dystrophy (DMD), Becker's muscular dystrophy, Congenital muscular dystrophy, Distal muscular dystrophy, Emery-Dreifuss' muscular dystrophy, Facio-scapulo-humeral muscular dystrophy, Limb-girdle muscular dystrophy, myotonic muscular dystrophy, oculopharyngeal muscular dystrophy, non-mitochondrial myopathies, myotonia, congenital myopathies selected from nemaline myopathy, multi/minicore myopathy and centronuclear myopathy, metabolic myopathies, inflammatory myopathies, muscle stem cell senescence caused by nutritional deficiencies, chronic obstructive pulmonary disease, cachexia of cancer, diseases resulting from clinical treatments with anthracyclines and/or for promoting muscle tissue growth and/or repair after graft, and wherein said mitochondrial UPR mt  inducing agent selected from nicotinamide riboside (NR), thiamphenicol (TAP) and analogues thereof. 
     
     
         3 . A method of preventing and/or treating of diseases or disorders associated with skeletal MuSCs senescence and/or decreased MuSCs number, wherein said diseases or disorders are selected from Duchenne's muscular dystrophy (DMD), Becker's muscular dystrophy, Congenital muscular dystrophy, Distal muscular dystrophy, Emery-Dreifuss' muscular dystrophy, Facio-scapulo-humeral muscular dystrophy, Limb-girdle muscular dystrophy, myotonic muscular dystrophy, oculopharyngeal muscular dystrophy, non-mitochondrial myopathies, myotonia, congenital myopathies selected from nemaline myopathy, multi/minicore myopathy and centronuclear myopathy, metabolic myopathies, inflammatory myopathies, muscle stem cell senescence caused by nutritional deficiencies, chronic obstructive pulmonary disease, cachexia of cancer, diseases resulting from clinical treatments with anthracyclines and/or for promoting muscle tissue growth and/or repair after graft in a subject, said method comprising administering an effective amount of a mitochondrial UPR mt  inducing agent selected from nicotinamide riboside (NR), thiamphenicol (TAP) and analogues thereof or a pharmaceutical composition thereof to a subject. 
     
     
         4 . The method according to  claim 3 , wherein the subject is suffering from a non-mitochondrial myopathy. 
     
     
         5 . The method according to  claim 3 , wherein the MuSCs senescence is a muscle dystrophy or muscle wasting. 
     
     
         6 . The method according to  claim 3 , wherein the MuSCs senescence is muscle frailty and sarcopenia in aging. 
     
     
         7 . The method according to  claim 3 , wherein said mitochondrial UPR mt  inducing agent is to be administered orally. 
     
     
         8 . The method according to  claim 3 , wherein said mitochondrial UPR mt  inducing agent is to be administered parenterally. 
     
     
         9 . The method according to  claim 3 , wherein said mitochondrial UPR mt  inducing agent is nicotinamide riboside (NR). 
     
     
         10 . The method according to  claim 3 , wherein said mitochondrial UPR mt  inducing agent is thiamphenicol (TAP) or analogues thereof. 
     
     
         11 . The method according to  claim 3 , wherein said mitochondrial UPR mt  inducing agent is to be administered in combination with a co-agent useful for preventing or treating a disease or disorder associated with MuSCs senescence and/or decreased MuSCs number. 
     
     
         12 . The method according to  claim 11 , wherein said co-agent is selected from an inhibitor of transforming growth factor β (TGFβ) family protein/receptor, a myostatin inhibitor, a follistatin-derived peptide, FS I-I, P38, a JAK-STAT signalling pathway inhibitor, SB203580, SB202190, BIRB796, AG490, 5,15-Diphenylporphyrin, a muscle stem cell activator, a Notch signalling activator, an anabolic stimulator of the muscle, and IGF-1.