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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.

Pubmed ID: 18310078

Authors

  • Wooldridge AA
  • Fortner CN
  • Lontay B
  • Akimoto T
  • Neppl RL
  • Facemire C
  • Datto MB
  • Kwon A
  • McCook E
  • Li P
  • Wang S
  • Thresher RJ
  • Miller SE
  • Perriard JC
  • Gavin TP
  • Hickner RC
  • Coffman TM
  • Somlyo AV
  • Yan Z
  • Haystead TA

Journal

The Journal of biological chemistry

Publication Data

April 25, 2008

Associated Grants

  • Agency: NHLBI NIH HHS, Id: 5 R01 HL078795-04
  • Agency: NIDDK NIH HHS, Id: DK065954-02
  • Agency: NIAMS NIH HHS, Id: R01 AR050429

Mesh Terms

  • Animals
  • Cyclic AMP-Dependent Protein Kinases
  • Cyclic GMP-Dependent Protein Kinases
  • Female
  • Gene Deletion
  • Humans
  • Mice
  • Models, Biological
  • Muscle Fibers, Skeletal
  • Muscle Proteins
  • Muscle, Smooth, Vascular
  • Myosins
  • Phenotype
  • Phosphoproteins
  • Phosphorylation
  • Physical Conditioning, Animal