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Altering muscle hypertrophy and atrophy by suppressing the functions of growth differentiation factors 8 (myostatin) and 11

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Item Summary

Title: Altering muscle hypertrophy and atrophy by suppressing the functions of growth differentiation factors 8 (myostatin) and 11
Authors: Hussein, Ahmed Mohamed Abd All
Keywords: biomechanically
Issue Date: Aug 2013
Publisher: [Honolulu] : [University of Hawaii at Manoa], [August 2013]
Abstract: Meat production in agricultural animals is mainly determined by muscle growth, since muscle tissue is the major component of meat. Meat production also is affected by bone growth, where, dynamic factors such as skeletal elongation and functional demands represent definite stimuli for muscle growth. Growth in length of a muscle correlates with the lengthening of the bone to which it is attached and biomechanically linked. Therefore, promoting muscle growth as well as bone growth in eat-producing animals is likely to improve the efficiency of meat production.
Recently, two highly homologous members of the transforming growth factor-ß (TGF-ß) superfamily, growth differentiation factor-8 (GDF8, also called myostatin) and-11 (GDF11), have been identified to play remarkable roles in muscle growth and bone development, respectively. Myostatin normally acts to limit muscle growth while GDF11 is essential for normal skeletal formation and development.
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. In order to investigate the possible functional redundancy of myostatin and GDF11, we produced the Mstn-Pro and Gdf11-Pro double transgenic mice by crossing two heterozygous transgenic mice (MstnPro+/-with Gdf11Pro+/-) to examine their effects on growth performances and muscle mass properties. Mice were born at the expected ratio of sex and transgenic animals. A dramatic muscling phenotype was observed in double transgenic mice carrying both myostatin and GDF11 pro-peptide. Expressions of both pro-peptides resulted 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 propeptide 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 as shown in hind and fore limbs and trunk parts. The double transgenic mice have a significant (P<0.01) increase of their carcass weight, hind limbs, fore limbs and trunk weight compared with GDF11-pro and WT mice, but the increase was not significant when compared with MSTN-Pro in both males and females mice. Over expression of both MSTN and GDF11 pro-peptides in double transgenic mice dramatically increase individual muscle weight (Longissimusdorsi, 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. These results demonstrate the significantly enhanced and double effects of the both MSTN and GDF11 propeptide transgenes on skeletal muscle growth and carcass muscle mass.
On the other hand, during food deprivation (FD), skeletal muscle protein is broken down to produce amino acids for hepatic gluconeogenesis to maintain blood glucose levels. However, to investigate, myostatin (MSTN) role in muscle atrophy induced by FD, we therefore examined expression and function of MSTN after two days of FD in both WT and MSTN-Pro transgenic mice . FD significantly (P<0.05)decreased body weight after one day in wiled-type mice but not in MSTN-Pro transgenic mice, however, after two days of the body weight decreased (P<0.05) in both wild-type and MSTN-Pro transgenic mice but the decrease was higher in wild-type (20% vs. 12%). Carcass, carcass parts weights and muscles mass decreased after two days of FD in both wild-type and MSTN-Pro transgenic mice, but the decrease was higher in wild-type compared with MSTN-Pro transgenic mice. mRNA levels of ubiquitin ligases MuRF-1 and atrogin-1 increased in fast-twitch tibialis anterior (TA) after two days of FD in both MSTN-Pro and wild-type mice, however the increase was significantly (P<0.05) higher in wild-type mice. MSTN mRNA levels were significantly increased approximately 2.3 folds in wild-type mice by 2 days of FD, but no remarkable increase was found in MSTN-Pro mice. Changes in hepatic enzyme expression in response to FD were identical between wild-type and MSTN-Pro transgenic mice. Our data are consistent with the hypothesis that MSTN is important for the initial atrophy occurring in response to FD.
Description: Ph.D. University of Hawaii at Manoa 2013.
Includes bibliographical references.
URI/DOI: http://hdl.handle.net/10125/100600
Appears in Collections:Ph.D. - Molecular Biosciences and Bioengineering



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