Abstract
BackgroundMyostatin, a member of the TGFβ superfamily, is well known as a potent and specific negative regulator of muscle growth. Targeting the myostatin signalling pathway may offer promising therapeutic strategies for the treatment of muscle-wasting disorders. In the last decade, various myostatin-binding proteins have been identified to be able to inhibit myostatin activity. One of these is GASP1 (Growth and Differentiation Factor-Associated Serum Protein-1), a protein containing a follistatin domain as well as multiple domains associated with protease inhibitors. Despite in vitro data, remarkably little is known about in vivo functions of Gasp1. To further address the role of GASP1 during mouse development and in adulthood, we generated a gain-of-function transgenic mouse model that overexpresses Gasp1 under transcriptional control of the human cytomegalovirus immediate-early promoter/enhancer.ResultsOverexpression of Gasp1 led to an increase in muscle mass observed not before day 15 of postnatal life. The surGasp1 transgenic mice did not display any other gross abnormality. Histological and morphometric analysis of surGasp1 rectus femoris muscles revealed an increase in myofiber size without a corresponding increase in myofiber number. Fiber-type distribution was unaltered. Interestingly, we do not detect a change in total fat mass and lean mass. These results differ from those for myostatin knockout mice, transgenic mice overexpressing the myostatin propeptide or follistatin which exhibit both muscle hypertrophy and hyperplasia, and show minimal fat deposition.ConclusionsAltogether, our data give new insight into the in vivo functions of Gasp1. As an extracellular regulatory factor in the myostatin signalling pathway, additional studies on GASP1 and its homolog GASP2 are required to elucidate the crosstalk between the different intrinsic inhibitors of the myostatin.
Highlights
Myostatin, a member of the TGFβ superfamily, is well known as a potent and specific negative regulator of muscle growth
Estimation of the amount of GDF8 associating with Growth and differentiation factor-associated serum protein-1 (GASP1) will be an important issue, providing mechanistic insights into this association
We are currently crossing our transgenic mice overexpressing Gasp1 on the myostatin null background to investigate if GASP1 stimulates muscle growth by additional mechanisms independent of myostatin inhibition like it has been shown in transgenic mice overexpressing follistatin presenting a quadrupling of muscle mass [15]
Summary
A member of the TGFβ superfamily, is well known as a potent and specific negative regulator of muscle growth. Various myostatin-binding proteins have been identified to be able to inhibit myostatin activity One of these is GASP1 (Growth and Differentiation Factor-Associated Serum Protein-1), a protein containing a follistatin domain as well as multiple domains associated with protease inhibitors. Growth and differentiation factor-associated serum protein-1 (GASP1; called WFIKKN2) is a secreted protein that contains multiple domains associated with protease-inhibitory proteins including a whey acidic protein domain, a Kazal domain, two Kunitz domains, and a netrin domain It contains a highly conserved module of cysteine-rich sequence termed the follistatin domain. GASP1 is primarily expressed in the ovary, testis, and brain while GASP2 is in the pancreas, liver, and thymus [20] To date, despite these data, little is known about the precise in vivo functions and protein interactions of these GASP proteins. Detailed phenotypic characterization shows muscle abnormalities but no obvious defects in other major organ systems
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