Transgenic overexpression of pregnancy-associated plasma protein-A in skeletal muscle of mice increases myofiber size and central nucleation in sedentary muscle and promotes muscle regeneration in the injured muscle

Abstract

ObjectiveWhile there is compelling evidence for an anabolic role of PAPP-A, an IGFBP protease, in muscle development, its effect on dynamic regulation of muscle regeneration has not been investigated. In this study, we evaluated the effect of transgenic PAPP-A overexpression in skeletal muscle of mice on myofiber formation in intact and crush-injured tibialus anterior muscle. DesignSkeletal muscle in transgenic mice overexpressing human PAPP-A in skeletal muscle was subjected to crush-injury. Myofiber formation and myogenic gene expression were then evaluated in injured or intact muscle of PAPP-A transgenic mice and wild-type mice. ResultsIn the intact muscle, aging PAPP-A transgenic (Tg.) mice (age of 12months) showed more than a 2-fold increase in both myofiber size and number of nuclei per myofiber compared with their wild-type (Wt.) littermates. Myofibers with centered nuclei, a hallmark of muscle regeneration, were increased from <1% in Wt. mice to 65% in Tg. muscle. In the injured muscle, reduced inflammatory cell infiltration and increased new myofiber size and the area occupied by new myofibers were observed in PAPP-A transgenic mice compared to wild-type littermates. MyoD and creatine kinase in the injured muscle was also significantly increased in the Tg. mice. Although TNF-α induced PAPP-A expression in skeletal myoblast culture and its expression increased upon injury, abrogation of TNF-α signaling in TNF-α receptor knockout mice had no impact on the extent of injury induction of PAPP-A. We also found that TGF-β expression was significantly increased following muscle injury in vivo and treatment with recombinant TGF-β in vitro significantly enhanced PAPP-A expression in skeletal myoblasts. ConclusionOur findings demonstrate that exogenous PAPP-A can promote recovery of muscle injury in aging mice albeit the expression of endogenous PAPP-A had already been increased dramatically upon muscle injury.