| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Cardiovascular and Metabolic Diseases Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, Pennington, New Jersey 08534
To whom requests for reprints should be addressed at 1 Bristol-Myers Squibb Company, Pharmaceutical Research Institute, Route 206 and Provinceline Road, Princeton, NJ 08543. E-mail: blake.beehler{at}bms.com
The ubiquitin-proteasome system is the primary proteolytic pathway implicated in skeletal muscle atrophy under catabolic conditions. Although several studies showed that proteasome inhibitors reduced proteolysis under catabolic conditions, few studies have demonstrated the ability of these inhibitors to preserve skeletal muscle mass and architecture in vivo. To explore this, we studied the effect of the proteasome inhibitor Velcade (also known as PS-341 and bortezomib) in denervated skeletal muscle in rats. Rats were given vehicle or Velcade (3 mg/kg po) daily for 7 days beginning immediately after induction of muscle atrophy by crushing the sciatic nerve. At the end of the study, the rats were euthanized and the soleus and extensor digitorum longus (EDL) muscles were harvested. In vehicle-treated rats, denervation caused a 33.5 ± 2.8% and 16.2 ± 2.7% decrease in the soleus and EDL muscle wet weights (% atrophy), respectively, compared to muscles from the contralateral (innervated) limb. Velcade significantly reduced denervation-induced atrophy to 17.1 ± 3.3% in the soleus (P < 0.01), a 51.6% reduction in atrophy associated with denervation, with little effect on the EDL (9.8 ± 3.2% atrophy). Histology showed a preservation of muscle mass and preservation of normal cellular architecture after Velcade treatment. Ubiquitin mRNA levels in denervated soleus muscle at the end of the study were significantly elevated 120 ± 25% above sham control levels and were reduced to control levels by Velcade. In contrast, testosterone proprionate (3 mg/kg sc) did not alleviate denervation-induced skeletal muscle atrophy but did prevent castration-induced levator ani atrophy, while Velcade was without effect. These results show that proteasome inhibition attenuates denervation-induced muscle atrophy in vivo in soleus muscles. However, this mechanism may not be operative in all types of atrophy.
Key Words: ubiquitin-proteasome pathway • Velcade • PS-341 • skeletal muscle atrophy • sarcopenia • muscle denervation
This article has been cited by other articles:
|
|
 |
|
  H. W. H. van Hees, Y.-P. Li, C. A. C. Ottenheijm, B. Jin, C. J. C. Pigmans, M. Linkels, P. N. R. Dekhuijzen, and L. M. A. Heunks Proteasome inhibition improves diaphragm function in congestive heart failure rats Am J Physiol Lung Cell Mol Physiol, June 1, 2008; 294(6): L1260 - L1268. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Szerafin, K. Hoetzenecker, S. Hacker, A. Horvath, A. Pollreisz, P. Arpad, A. Mangold, T. Wliszczak, M. Dworschak, R. Seitelberger, et al. Heat Shock Proteins 27, 60, 70, 90{alpha}, and 20S Proteasome in On-Pump Versus Off-Pump Coronary Artery Bypass Graft Patients Ann. Thorac. Surg., January 1, 2008; 85(1): 80 - 87. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. A. C. Ottenheijm, L. M. A. Heunks, and P. N. R. Dekhuijzen Diaphragm Muscle Fiber Dysfunction in Chronic Obstructive Pulmonary Disease: Toward a Pathophysiological Concept Am. J. Respir. Crit. Care Med., June 15, 2007; 175(12): 1233 - 1240. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. A. C. Ottenheijm, L. M. A. Heunks, Y.-P. Li, B. Jin, R. Minnaard, H. W. H. van Hees, and P. N. R. Dekhuijzen Activation of the Ubiquitin-Proteasome Pathway in the Diaphragm in Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., November 1, 2006; 174(9): 997 - 1002. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. G. Dickhout and R. C. Austin Proteasomal Regulation of Cardiac Hypertrophy: Is Demolition Necessary for Building? Circulation, October 24, 2006; 114(17): 1796 - 1798. [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
