Deletion of the Protein Kinase A/Protein Kinase G Target SMTNL1 Promotes an Exercise-adapted Phenotype in Vascular Smooth Muscle*S⃞

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 α-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

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 con- tractile 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. Originally published Journal of Biological Chemistry Vol. 283 No. 17 Apr 200

Adipocytes Under Environmental Assault: Targets for Obesity?

Abstract In the recent years, there has been a tremendous concern over the possible health threat posed by endocrine-disrupting chemicals (EDCs). These are mostly synthetic chemicals found in various materials such as organo-chlorinated pesticides, industrial chemicals, plastics and plasticizers, fuels, heavy metals, additives or contaminants in food, and personal care products. These chemicals are present in the environment and are with widespread use. Human exposure to EDCs occurs via ingestion of food, dust and water, via inhalation of gases and particles in the air, and through the skin. Data from several animal models, human clinical observations, and epidemiological studies converge to implicate their association with altered reproductive function in males and females, increased incidence of breast cancer, abnormal growth patterns and neuro-developmental delays in children, disruption of adipocyte function, as well as changes in immune function. The EDCs exert their insulting effects by interfering with hormone biosynthesis, metabolism, or action resulting in a deviation from normal homeostatic control or reproduction. The mechanisms of EDCs involve divergent pathways including (but not limited to) estrogenic, anti-androgenic, thyroid, peroxisome proliferator-activated receptor c, retinoid, and actions through other nuclear receptors; steroidogenic enzymes; neurotransmitter receptors and systems; and many other pathways that are highly conserved in wildlife and humans. Emerging data from in vitro as well as in vivo models suggest new targets (i.e. adipocyte differentiation and mechanisms involved in weight homeostasis) of abnormal programming by EDCs, and provide strong evidence to support the scientific term ‘obesogen’. The emerging idea of a link between EDCs and obesity expands the focus on obesity from intervention and treatment to include prevention and avoidance of these chemical modifiers. Because expansion of the adipocyte pool is critical for safely storing excess lipid, an understanding how these signaling axes can be altered by EDCs is critical in appreciating how environmental contaminants might contribute to the development of metabolic diseases