(P32-026-23) Synergistic Effects of Double Transgenes of Myostatin and GDF11 Propeptides on Growth Performances and Muscle Mass

Objectives: Myostatin (MSTN) and growth differentiation factor-11 (GDF11) are closely related proteins involved in cell growth and differentiation in vertebrate animals. Both MSTN and GDF11 negatively regulate cell proliferation and differentiation. Despite their high degrees of sequence identity, inhibitions of these genes result in non-overlapping phenotypes affecting distinct biological processes. Loss of Mstn in mice causes a doubling of skeletal muscle mass while loss of GDF11 in mice causes dramatic anterior homeotic transformations of the axial skeleton. The objective is to investigate the possible functional redundancy of myostatin and GDF11, and the effects of inhibiting both genes on growth performances and muscle mass properties.

Methods: We produced the Mstn-Pro and Gdf11-Pro double transgenic mice by crossing two heterozygous transgenic mice (MstnPro+/- with Gdf11Pro+/-). Forty male and forty female mice were used in this study. The animals were given unrestricted access to a normal fat diet until 16 weeks of age.

Results: A dramatic muscling phenotype was observed in double transgenic mice carrying both MSTN and GDF11 pro-peptides. resulting in a 37% and 31% increase in body weight (P < 0. 01) in both males and females, respectively, where the expression of MSTN pro-peptide alone increased the body weight by 24% and 21% (P < 0. 01) in both males and females, respectively. However, the body weight increase by GDF11 pro-peptide expression was only 8% and 11% over the wild-type (WT) control males and females, respectively. Extreme muscling was present throughout the whole carcass of transgenic mice. Over- expression of both MSTN and GDF11 pro-peptides dramatically increase individual muscle weight (Longissimus dorsi, Gluteus medius, Vastus lateralis, Biceps femoris, Gastrocnemius, and Triceps, P< 0.05) compared with GDF11-Pro and WT mice in both males and females. The double transgenic males showed significant (P < 0.05) lower level of MSTN, Atrogin-1 and MuRF1 mRNA in muscle tissue compared with wild-type males.

Conclusions: These results demonstrate the significantly enhanced and double effects of both MSTN and GDF11 propeptide transgenes on skeletal muscle growth and muscle mass.

Funding Sources: USDA multi-state Hatch project and USDA-Centre for Tropical and Subtropical Aquaculture in Hawaii.