Adeno-Associated Virus-8-Mediated Intravenous Transfer of Myostatin Propeptide Leads to Systemic Functional Improvements of Slow but Not Fast Muscle

被引:21
作者
Foster, Keith [1 ]
Graham, Ian R. [1 ]
Otto, Anthony [2 ]
Foster, Helen [1 ]
Trollet, Capucine [1 ]
Yaworsky, Paul J. [3 ]
Walsh, Frank S. [3 ]
Bickham, Dale [4 ]
Curtin, Nancy A. [4 ]
Kawar, Susannah L. [1 ]
Patel, Ketan [2 ]
Dickson, George [1 ]
机构
[1] Royal Holloway Univ London, Sch Biol Sci, SWAN Inst Biomed & Life Sci, Egham TW20 0EX, Surrey, England
[2] Univ Reading, Sch Biol Sci, Reading, Berks, England
[3] Wyeth Res, Clin Discovery, Collegeville, PA USA
[4] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London, England
关键词
VIRUS SEROTYPE-8 VECTORS; SKELETAL-MUSCLE; MYOBLAST PROLIFERATION; NEGATIVE REGULATOR; DYSTROPHIC MUSCLE; SELF-RENEWAL; STEM-CELL; GROWTH; MICE; GENE;
D O I
10.1089/rej.2008.0815
中图分类号
R592 [老年病学]; C [社会科学总论];
学科分类号
03 ; 0303 ; 100203 ;
摘要
Myostatin is a member of the transformating growth factor-beta (TGF-beta) superfamily of proteins and is produced almost exclusively in skeletal muscle tissue, where it is secreted and circulates as a serum protein. Myostatin acts as a negative regulator of muscle mass through the canonical SMAD2/3/4 signaling pathway. Naturally occurring myostatin mutants exhibit a 'double muscling' phenotype in which muscle mass is dramatically increased as a result of both hypertrophy and hyperplasia. Myostatin is naturally inhibited by its own propeptide; therefore, we assessed the impact of adeno-associated virus-8 (AAV8) myostatin propeptide vectors when systemically introduced in MF-1 mice. We noted a significant systemic increase in muscle mass in both slow and fast muscle phenotypes, with no evidence of hyperplasia; however, the nuclei-to-cytoplasm ratio in all myofiber types was significantly reduced. An increase in muscle mass in slow (soleus) muscle led to an increase in force output; however, an increase in fast (extensor digitorum longus [EDL]) muscle mass did not increase force output. These results suggest that the use of gene therapeutic regimens of myostatin inhibition for age-related or disease-related muscle loss may have muscle-specific effects.
引用
收藏
页码:85 / 93
页数:9
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