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Transgenic Overexpression of Pregnancy-Associated Plasma Protein-A Increases the Somatic Growth and Skeletal Muscle Mass in Mice

Musculoskeletal Disease Center (M.R., S.M., J.E.W., B.B., K.T., D.H., D.P., X.Q.), Laboratory for Skeletal Muscle Physiology and Neurobiology (A.K.), Jerry L. Pettis Memorial Veterans Affairs Medical Center, and Departments of Medicine (S.M., J.E.W., A.K., X.Q.), Biochemistry (S.M.), Physiology (S.M.), Loma Linda University, Loma Linda, California 92357

Address all correspondence and requests for reprints to: Xuezhong Qin, Ph.D., Musculoskeletal Disease Center, J. L. Pettis Veterans Affairs Medical Center (151), 11201 Benton Street, Loma Linda, California 92357. E-mail: xuezhong.qin{at}med.va.gov.

Although IGFs are indispensable to skeletal muscle development, little information is available regarding the mechanisms regulating the local action of IGFs in skeletal muscle tissues. Here we tested the hypothesis that pregnancy-associated plasma protein-A (PAPP-A), a member of the metalloproteinase superfamily, promotes skeletal muscle formation in vivo through degrading IGF binding proteins (IGFBPs), which increases the bioavailability of IGFs. Expression of PAPP-A is significantly increased in muscle five days after muscle injury in mice. Targeted overexpression of PAPP-A using a muscle-specific promoter significantly increased the prenatal/postnatal growth, skeletal muscle weight, and muscle fiber area in mice. These anabolic effects were reproduced using F2/F3 progeny. Free IGF-I concentration was severalfold higher in the conditioned medium (CM) of ex vivo cultured muscle from the transgenic mice, compared with the wild-type littermate muscle. Accordingly, the proliferation of C2C12 myoblasts was significantly increased in the presence of CM from cultured skeletal muscle of the transgenic mice, compared with the controls. This observed increase in myoblast proliferation was abolished on addition of noncleavable IGFBP-4 peptide, which reduced free IGF-I concentration back to the basal level of the wild-type CM. Furthermore, proliferation and differentiation of C2C12 myoblasts was increased by transient overexpression of proteolytically active PAPP-A but not by inactive mutant PAPP-A (E483/A). Collectively, we identified PAPP-A as a novel regulator of prenatal/postnatal growth and skeletal muscle formation in vivo. Moreover, our studies provide the first experimental evidence that IGFBP degradation is a key determinant in modulating the local action of IGFs in muscle.