Ectopic expression of myostatin induces atrophy of adult skeletal muscle by decreasing muscle gene expression.
Myostatin is a master regulator of myogenesis and early postnatal skeletal muscle growth. However, myostatin has been also involved in several forms of muscle wasting in adulthood, suggesting a functional role for myostatin in the regulation of skeletal muscle mass in adult. In the present study, localized ectopic expression of myostatin was achieved by gene electrotransfer of a myostatin expression vector into the tibialis anterior muscle of adult Sprague Dawley male rats. The corresponding empty vector was electrotransfected in contralateral muscle. Ectopic myostatin mRNA was abundantly present in muscles electrotransfected with myostatin expression vector, whereas it was undetectable in contralateral muscles. Overexpression of myostatin elicited a significant decrease in muscle mass (10 and 20% reduction 7 and 14 d after gene electrotransfer, respectively), muscle fiber cross-sectional area (15 and 30% reduction 7 and 14 d after gene electrotransfer, respectively), and muscle protein content (20% reduction). No decrease in fiber number was observed. Overexpression of myostatin markedly decreased the expression of muscle structural genes (myosin heavy chain IIb, troponin I, and desmin) and the expression of myogenic transcription factors (MyoD and myogenin). Incidentally, mRNA level of caveolin-3 and peroxisome proliferator activated receptor gamma coactivator-1alpha was also significantly decreased 14 d after myostatin gene electrotransfer. To conclude, our study demonstrates that myostatin-induced muscle atrophy elicits the down-regulation of muscle-specific gene expression. Our observations support an important role for myostatin in muscle atrophy in physiological and physiopathological situations where myostatin expression is induced.
Durieux
Anne-Cécile
AC
Unité Physiologie et Physiopathologie de l'Exercice et Handicap, Université Jean Monnet, 42023 Saint-Etienne cedex 2, France.
Amirouche
Adel
A
Banzet
Sébastien
S
Koulmann
Nathalie
N
Bonnefoy
Régis
R
Pasdeloup
Marielle
M
Mouret
Catherine
C
Bigard
Xavier
X
Peinnequin
André
A
Freyssenet
Damien
D
D000818:Animals; D051244:Caveolin 3 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D005822:Genetic Vectors / Q000235:genetics; D015151:Immunoblotting; D008297:Male; D024510:Muscle Development / Q000235:genetics; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D009133:Muscular Atrophy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017570:MyoD Protein / Q000235:genetics / Q000378:metabolism; D018008:Myogenin / Q000235:genetics / Q000378:metabolism; D055435:Myostatin; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000502:physiology*
C495549:Cav3 protein, rat; D051244:Caveolin 3; C525913:Mstn protein, rat; D017570:MyoD Protein; D018008:Myogenin; D055435:Myostatin; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D016212:Transforming Growth Factor beta