title: Chronic Treatment with the AMPK Agonist AICAR Prevents Skeletal Muscle Pathology but Fails to Improve Clinical Outcome in a Mouse Model of Severe Spinal Muscular Atrophy.
abstract: Spinal muscular atrophy (SMA) is a genetic neuromuscular disorder characterized by spinal and brainstem motor neuron (MN) loss and skeletal muscle paralysis. Currently, there is no effective treatment other than supportive care to ameliorate the quality of life of patients with SMA. Some studies have reported that physical exercise, by improving muscle strength and motor function, is potentially beneficial in SMA. The adenosine monophosphate-activated protein kinase agonist 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) has been reported to be an exercise mimetic agent that is able to regulate muscle metabolism and increase endurance both at rest and during exercise. Chronic AICAR administration has been shown to ameliorate the dystrophic muscle phenotype and motor behavior in the mdx mouse, a model of Duchenne muscular dystrophy. Here, we investigated whether chronic AICAR treatment was able to elicit beneficial effects on motor abilities and neuromuscular histopathology in a mouse model of severe SMA (the SMNΔ7 mouse). We report that AICAR improved skeletal muscle atrophy and structural changes found in neuromuscular junctions of SMNΔ7 animals. However, although AICAR prevented the loss of glutamatergic excitatory synapses on MNs, this compound was not able to mitigate MN loss or the microglial and astroglial reaction occurring in the spinal cord of diseased mice. Moreover, no improvement in survival or motor performance was seen in SMNΔ7 animals treated with AICAR. The beneficial effects of AICAR in SMA found in our study are SMN-independent, as no changes in the expression of this protein were seen in the spinal cord and skeletal muscle of diseased animals treated with this compound.
authors.affiliation: Unitat de Neurobiologia Cel·lular, Departament de Medicina Experimental, Facultat de Medicina, Universitat de Lleida and Institut de Recerca Biomèdica de Lleida (IRBLLEIDA), Av. Rovira Roure 80, 25198, Lleida, Catalonia, Spain.
authors.forename: Clàudia
authors.initials: C
authors.lastname: Cerveró
authors.affiliation: Unitat de Neurobiologia Cel·lular, Departament de Medicina Experimental, Facultat de Medicina, Universitat de Lleida and Institut de Recerca Biomèdica de Lleida (IRBLLEIDA), Av. Rovira Roure 80, 25198, Lleida, Catalonia, Spain.
authors.forename: Neus
authors.initials: N
authors.lastname: Montull
authors.affiliation: Unitat de Neurobiologia Cel·lular, Departament de Medicina Experimental, Facultat de Medicina, Universitat de Lleida and Institut de Recerca Biomèdica de Lleida (IRBLLEIDA), Av. Rovira Roure 80, 25198, Lleida, Catalonia, Spain.
authors.forename: Olga
authors.initials: O
authors.lastname: Tarabal
authors.affiliation: Unitat de Neurobiologia Cel·lular, Departament de Medicina Experimental, Facultat de Medicina, Universitat de Lleida and Institut de Recerca Biomèdica de Lleida (IRBLLEIDA), Av. Rovira Roure 80, 25198, Lleida, Catalonia, Spain.
authors.forename: Lídia
authors.initials: L
authors.lastname: Piedrafita
authors.affiliation: Unitat de Neurobiologia Cel·lular, Departament de Medicina Experimental, Facultat de Medicina, Universitat de Lleida and Institut de Recerca Biomèdica de Lleida (IRBLLEIDA), Av. Rovira Roure 80, 25198, Lleida, Catalonia, Spain.
authors.forename: Josep E
authors.initials: JE
authors.lastname: Esquerda
authors.affiliation: Unitat de Neurobiologia Cel·lular, Departament de Medicina Experimental, Facultat de Medicina, Universitat de Lleida and Institut de Recerca Biomèdica de Lleida (IRBLLEIDA), Av. Rovira Roure 80, 25198, Lleida, Catalonia, Spain. jordi.caldero@mex.udl.cat.
authors.forename: Jordi
authors.initials: J
authors.lastname: Calderó
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000187:drug effects / Q000473:pathology*; D009134:Muscular Atrophy, Spinal / Q000188:drug therapy* / Q000473:pathology; D012265:Ribonucleotides / Q000627:therapeutic use*; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide
keywords: AICAR; Neuromuscular junction; SMNΔ7 mouse; Skeletal muscle; Spinal cord; Spinal muscular atrophy