Muscle-specific AMPK ß1ß2-null mice display a myopathy due to loss of capillary density in nonpostural muscles.
FASEB J
; 28(5): 2098-107, 2014 May.
Article
em En
| MEDLINE
| ID: mdl-24522207
ABSTRACT
AMP-activated protein kinase (AMPK) is a master regulator of metabolism. While muscle-specific AMPK ß1ß2 double-knockout (ß1ß2M-KO) mice display alterations in metabolic and mitochondrial capacity, their severe exercise intolerance suggested a secondary contributor to the observed phenotype. We find that tibialis anterior (TA), but not soleus, muscles of sedentary ß1ß2M-KO mice display a significant myopathy (decreased myofiber areas, increased split and necrotic myofibers, and increased centrally nucleated myofibers. A mitochondrial- and fiber-type-specific etiology to the myopathy was ruled out. However, ß1ß2M-KO TA muscles displayed significant (P<0.05) increases in platelet aggregation and apoptosis within myofibers and surrounding interstitium (P<0.05). These changes correlated with a 45% decrease in capillary density (P<0.05). We hypothesized that the ß1ß2M-KO myopathy in resting muscle resulted from impaired AMPK-nNOSµ signaling, causing increased platelet aggregation, impaired vasodilation, and, ultimately, ischemic injury. Consistent with this hypothesis, AMPK-specific phosphorylation (Ser1446) of nNOSµ was decreased in ß1ß2M-KO compared to wild-type (WT) mice. The AMPK-nNOSµ relationship was further demonstrated by administration of 5-aminoimidazole-4-carboxamide 1-ß-D-ribofuranoside (AICAR) to ß1ß2-MKO muscles and C2C12 myotubes. AICAR significantly increased nNOSµ phosphorylation and nitric oxide production (P<0.05) within minutes of administration in WT muscles and C2C12 myotubes but not in ß1ß2M-KO muscles. These findings highlight the importance of the AMPK-nNOSµ pathway in resting skeletal muscle.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Capilares
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Músculo Esquelético
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Proteínas Quinases Ativadas por AMP
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Doenças Musculares
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Óxido Nítrico
Limite:
Animals
Idioma:
En
Revista:
FASEB J
Assunto da revista:
BIOLOGIA
/
FISIOLOGIA
Ano de publicação:
2014
Tipo de documento:
Article
País de afiliação:
Canadá