Double Transgenes of Myostatin and GDF11 Propeptides Lead to Further Growth and Muscle Mass Enhancement

Myostatin (MSTN) and growth differentiation factor-11 (GDF11) are highly related proteins in the regulation of musculoskeletal cell growth and differentiation. Despite their high degrees of sequence identity, knock-out of MSTN and GDF11 genes results in non-overlapping phenotypes affecting distinct biological processes.Previously, we employed propeptide transgenes to depress MSTN and GDF11 functions in mice.  To investigate the possible functional redundancy of myostatin and GDF11 on skeletal muscle growth, we produced Mstn-Pro and Gdf11-Pro double transgenic mice by crossing two heterozygous transgenic mice  (MstnPro^+/- and Gdf11Pro^+/-).   A dramatic muscling phenotype was observed in double transgenic mice carrying both myostatin and GDF11 propeptide transgenes. Expressions of both transgenes resulted in a 37% and 31% increase in body weight (P<0. 01) in males and females compared with wild-type littermates, respectively, where the expression of MSTN propeptide transgene alone increased the body weight by 24% and 21% (P<0.01) in males and females, respectively. However, the body weight increase by GDF11 propeptide expression was only 8% and 11% over the wild-type littermate males and females, respectively. Extreme muscling was present throughout the whole carcass of transgenic mice as shown in hind and fore limbs and trunk parts. The double transgenic mice have significant (P<0.01) increase in carcass weight, hind limbs, fore limbs and trunk weight compared with GDF11-pro and wild-type littermates, but the increase was not significant when compared with MSTN-Pro in both males and females mice.  The double transgenic mice showed significantly (P<0.05) lower level of MSTN, atrogin-1 and MuRF1 mRNA in muscle tissue compared with wild-type males. These results demonstrate significantly synergistic effects of MSTN and GDF11 propeptide transgenes on skeletal muscle growth and carcass muscle mass.