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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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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AMP-Activated Protein Kinases
Muscular Diseases
Muscle
Muscles
Skeletal Muscle Fibers
Platelet Aggregation
Phosphorylation
Skeletal Muscle
Platelets
Agglomeration
Vasodilation
Nitric Oxide
Metabolism
Apoptosis
Phenotype
Wounds and Injuries
Fibers

Cite this

Thomas, M. M., Wang, D. C., D'Souza, D. M., Krause, M. P., Layne, A. S., Criswell, D. S., ... 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
Thomas, Melissa M ; Wang, David C ; D'Souza, Donna M ; Krause, Matthew P ; Layne, Andrew S ; Criswell, David S ; O'Neill, Hayley M ; Connor, Michael K ; Anderson, Judy E ; Kemp, Bruce E ; Steinberg, Gregory R ; Hawke, Thomas J. / Muscle-specific AMPK β1β2-null mice display a myopathy due to loss of capillary density in nonpostural muscles. In: FASEB Journal. 2014 ; Vol. 28, No. 5. pp. 2098-107.
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title = "Muscle-specific AMPK β1β2-null mice display a myopathy due to loss of capillary density in nonpostural muscles",
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.",
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Thomas, MM, Wang, DC, D'Souza, DM, Krause, MP, Layne, AS, Criswell, DS, O'Neill, HM, Connor, MK, Anderson, JE, Kemp, BE, Steinberg, GR & Hawke, TJ 2014, 'Muscle-specific AMPK β1β2-null mice display a myopathy due to loss of capillary density in nonpostural muscles' FASEB Journal, vol. 28, no. 5, pp. 2098-107. https://doi.org/10.1096/fj.13-238972

Muscle-specific AMPK β1β2-null mice display a myopathy due to loss of capillary density in nonpostural muscles. / Thomas, Melissa M; Wang, David C; D'Souza, Donna M; Krause, Matthew P; Layne, Andrew S; Criswell, David S; O'Neill, Hayley M; Connor, Michael K; Anderson, Judy E; Kemp, Bruce E; Steinberg, Gregory R; Hawke, Thomas J.

In: FASEB Journal, Vol. 28, No. 5, 05.2014, p. 2098-107.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Muscle-specific AMPK β1β2-null mice display a myopathy due to loss of capillary density in nonpostural muscles

AU - Thomas, Melissa M

AU - Wang, David C

AU - D'Souza, Donna M

AU - Krause, Matthew P

AU - Layne, Andrew S

AU - Criswell, David S

AU - O'Neill, Hayley M

AU - Connor, Michael K

AU - Anderson, Judy E

AU - Kemp, Bruce E

AU - Steinberg, Gregory R

AU - Hawke, Thomas J

PY - 2014/5

Y1 - 2014/5

N2 - 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.

AB - 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.

U2 - 10.1096/fj.13-238972

DO - 10.1096/fj.13-238972

M3 - Article

VL - 28

SP - 2098

EP - 2107

JO - FASEB Journal

JF - FASEB Journal

SN - 0892-6638

IS - 5

ER -