Deletion of the protein kinase A/protein kinase G target SMTNL1 promotes an exercise-adapted phenotype in vascular smooth muscle.
In vivo protein kinases A and G (PKA and PKG) coordinately phosphorylate a broad range of substrates to mediate their various physiological effects. The functions of many of these substrates have yet to be defined genetically. Herein we show a role for smoothelin-like protein 1 (SMTNL1), a novel in vivo target of PKG/PKA, in mediating vascular adaptations to exercise. Aortas from smtnl1(-/-) mice exhibited strikingly enhanced vasorelaxation before exercise, similar in extent to that achieved after endurance training of wild-type littermates. Additionally, contractile responses to alpha-adrenergic agonists were greatly attenuated. Immunological studies showed SMTNL1 is expressed in smooth muscle and type 2a striated muscle fibers. Consistent with a role in adaptations to exercise, smtnl1(-/-) mice also exhibited increased type 2a fibers before training and better performance after forced endurance training compared smtnl1(+/+) mice. Furthermore, exercise was found to reduce expression of SMTNL1, particularly in female mice. In both muscle types, SMTNL1 is phosphorylated at Ser-301 in response to adrenergic signals. In vitro SMTNL1 suppresses myosin phosphatase activity through a substrate-directed effect, which is relieved by Ser-301 phosphorylation. Our findings suggest roles for SMTNL1 in cGMP/cAMP-mediated adaptations to exercise through mechanisms involving direct modulation of contractile activity.
Wooldridge
Anne A
AA
Department of Pharmacology, Medicine, Duke University, Medical Center, Durham, North Carolina 27710, USA.
Fortner
Christopher N
CN
Lontay
Beata
B
Akimoto
Takayuki
T
Neppl
Ronald L
RL
Facemire
Carie
C
Datto
Michael B
MB
Kwon
Ashley
A
McCook
Everett
E
Li
Ping
P
Wang
Shiliang
S
Thresher
Randy J
RJ
Miller
Sara E
SE
Perriard
Jean-Claude
JC
Gavin
Timothy P
TP
Hickner
Robert C
RC
Coffman
Thomas M
TM
Somlyo
Avril V
AV
Yan
Zhen
Z
Haystead
Timothy A J
TA
D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism*; D005260:Female; D017353:Gene Deletion; D006801:Humans; D051379:Mice; D008954:Models, Biological; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D009124:Muscle Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D009218:Myosins / Q000378:metabolism; D010641:Phenotype; D010750:Phosphoproteins / Q000235:genetics* / Q000502:physiology; D010766:Phosphorylation; D010805:Physical Conditioning, Animal; D000096985:Calponins
D017868:Cyclic AMP-Dependent Protein Kinases; D017869:Cyclic GMP-Dependent Protein Kinases; D009124:Muscle Proteins; D009218:Myosins; D010750:Phosphoproteins; C491838:SMTNL1 protein, mouse; D000096985:Calponins