First Author | Thomas MM | Year | 2014 |
Journal | FASEB J | Volume | 28 |
Issue | 5 | Pages | 2098-107 |
PubMed ID | 24522207 | Mgi Jnum | J:212041 |
Mgi Id | MGI:5577235 | Doi | 10.1096/fj.13-238972 |
Citation | Thomas MM, et al. (2014) Muscle-specific AMPK beta1beta2-null mice display a myopathy due to loss of capillary density in nonpostural muscles. FASEB J 28(5):2098-107 |
abstractText | AMP-activated protein kinase (AMPK) is a master regulator of metabolism. While muscle-specific AMPK beta1beta2 double-knockout (beta1beta2M-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 beta1beta2M-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, beta1beta2M-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 beta1beta2M-KO myopathy in resting muscle resulted from impaired AMPK-nNOSmu signaling, causing increased platelet aggregation, impaired vasodilation, and, ultimately, ischemic injury. Consistent with this hypothesis, AMPK-specific phosphorylation (Ser1446) of nNOSmu was decreased in beta1beta2M-KO compared to wild-type (WT) mice. The AMPK-nNOSmu relationship was further demonstrated by administration of 5-aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside (AICAR) to beta1beta2-MKO muscles and C2C12 myotubes. AICAR significantly increased nNOSmu phosphorylation and nitric oxide production (P<0.05) within minutes of administration in WT muscles and C2C12 myotubes but not in beta1beta2M-KO muscles. These findings highlight the importance of the AMPK-nNOSmu pathway in resting skeletal muscle. |