Muscle-specific AMPK β1β2-null mice display a myopathy due to loss of capillary density in nonpostural muscles

Melissa M Thomas, David C Wang, Donna M D'Souza, Matthew P Krause, Andrew S Layne, David S Criswell, Hayley M O'Neill, Michael K Connor, Judy E Anderson, Bruce E Kemp, Gregory R Steinberg, Thomas J Hawke

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18 Citations (Scopus)

Abstract

AMP-activated protein kinase (AMPK) is a master regulator of metabolism. While muscle-specific AMPK β1β2 double-knockout (β1β2M-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 β1β2M-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, β1β2M-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 β1β2M-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 β1β2M-KO compared to wild-type (WT) mice. The AMPK-nNOSμ relationship was further demonstrated by administration of 5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR) to β1β2-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 β1β2M-KO muscles. These findings highlight the importance of the AMPK-nNOSμ pathway in resting skeletal muscle.

Original languageEnglish
Pages (from-to)2098-107
Number of pages10
JournalFASEB Journal
Volume28
Issue number5
DOIs
Publication statusPublished - May 2014
Externally publishedYes

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    Thomas, M. M., Wang, D. C., D'Souza, D. M., Krause, M. P., Layne, A. S., Criswell, D. S., O'Neill, H. M., Connor, M. K., Anderson, J. E., Kemp, B. E., Steinberg, G. R., & Hawke, T. J. (2014). Muscle-specific AMPK β1β2-null mice display a myopathy due to loss of capillary density in nonpostural muscles. FASEB Journal, 28(5), 2098-107. https://doi.org/10.1096/fj.13-238972