Clenbuterol induces muscle-specific attenuation of atrophy through effects on the ubiquitin-proteasome pathway.
The ubiquitin-proteasome pathway is primarily responsible for myofibrillar protein degradation during hindlimb unweighting (HU). Beta-adrenergic agonists such as clenbuterol (CB) induce muscle hypertrophy and attenuate muscle atrophy due to disuse or inactivity. However, the molecular mechanism by which CB exerts these effects remains poorly understood. The aims of this study were to investigate whether CB attenuates HU-induced muscle atrophy through an inhibition of the ubiquitin-proteasome pathway and whether insulin-like growth factor I (IGF-I) mediates this inhibition. Rats were randomized to the following groups: weight-bearing control, 14-day CB-treated, 14-day HU, and CB + HU. HU-induced atrophy was associated with increased proteolysis and upregulation of components of the ubiquitin-proteasome pathway (ubiquitin conjugates, ubiquitin conjugating enzyme E2-14 kDa, and 20S proteasome activity). Upregulation of the ubiquitin proteasome occurred in all muscles tested but was more pronounced in muscles composed primarily of slow-twitch fibers (soleus) than in fast-twitch muscles (plantaris and tibialis anterior). Although CB induced hypertrophy in all muscles, CB attenuated the HU-induced atrophy and reduced ubiquitin conjugates only in the fast plantaris and tibialis anterior and not in the slow soleus muscle. CB did not elevate IGF-I protein content in either of the muscles examined. These results suggest that CB induces hypertrophy and alleviates HU-induced atrophy, particularly in the fast muscles, at least in part through a muscle-specific inhibition of the ubiquitin-proteasome pathway and that these effects are not mediated by the local production of IGF-I in skeletal muscle.
Yimlamai
Tossaporn
T
Department of Applied Physiology and Kinesiology, Univ. of Florida, Gainesville, FL, USA.
Dodd
Stephen L
SL
Borst
Stephen E
SE
Park
Sooyeon
S
D000284:Administration, Oral; D000818:Animals; D002976:Clenbuterol / Q000008:administration & dosage*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D019417:Hindlimb Suspension / Q000009:adverse effects; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D009133:Muscular Atrophy / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D025801:Ubiquitin / Q000378:metabolism*
D025801:Ubiquitin; D007334:Insulin-Like Growth Factor I; D046988:Proteasome Endopeptidase Complex; D002976:Clenbuterol