AMPK activation stimulates autophagy and ameliorates muscular dystrophy in the mdx mouse diaphragm.
Duchenne muscular dystrophy (DMD) is characterized by myofiber death from apoptosis or necrosis, leading in many patients to fatal respiratory muscle weakness. Among other pathological features, DMD muscles show severely deranged metabolic gene regulation and mitochondrial dysfunction. Defective mitochondria not only cause energetic deficiency, but also play roles in promoting myofiber atrophy and injury via opening of the mitochondrial permeability transition pore. Autophagy is a bulk degradative mechanism that serves to augment energy production and eliminate defective mitochondria (mitophagy). We hypothesized that pharmacological activation of AMP-activated protein kinase (AMPK), a master metabolic sensor in cells and on-switch for the autophagy-mitophagy pathway, would be beneficial in the mdx mouse model of DMD. Treatment of mdx mice for 4 weeks with an established AMPK agonist, AICAR (5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside), potently triggered autophagy in the mdx diaphragm without inducing muscle fiber atrophy. In AICAR-treated mdx mice, the exaggerated sensitivity of mdx diaphragm mitochondria to calcium-induced permeability transition pore opening was restored to normal levels. There were associated improvements in mdx diaphragm histopathology and in maximal force-generating capacity, which were not linked to increased mitochondrial biogenesis or up-regulated utrophin expression. These findings suggest that agonists of AMPK and other inducers of the autophagy-mitophagy pathway can help to promote the elimination of defective mitochondria and may thus serve as useful therapeutic agents in DMD.
Physiology and Experimental Medicine Heart-Muscle Unit, INSERM U1046, Montpellier 1 University, Montpellier, France.
Marion
M
Pauly
Frederic
F
Daussin
Yan
Y
Burelle
Tong
T
Li
Richard
R
Godin
Jeremy
J
Fauconnier
Christelle
C
Koechlin-Ramonatxo
Gerald
G
Hugon
Alain
A
Lacampagne
Marjorie
M
Coisy-Quivy
Feng
F
Liang
Sabah
S
Hussain
Stefan
S
Matecki
Basil J
BJ
Petrof
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001343:Autophagy; D003964:Diaphragm / Q000201:enzymology* / Q000473:pathology* / Q000503:physiopathology / Q000648:ultrastructure; D004734:Energy Metabolism / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D046912:Multiprotein Complexes; D009119:Muscle Contraction / Q000187:drug effects; D009137:Muscular Dystrophy, Animal / Q000201:enzymology* / Q000473:pathology* / Q000503:physiopathology; D010084:Oxidation-Reduction / Q000187:drug effects; D011506:Proteins / Q000378:metabolism; D012265:Ribonucleotides / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases
D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D046912:Multiprotein Complexes; D011506:Proteins; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide