Characterisation of isoprenaline myotoxicity on slow-twitch skeletal versus cardiac muscle.
BACKGROUND
Elevated catecholamines are known to be cardiotoxic, but their potential injurious effects on skeletal muscles are largely unknown. We have investigated whether isoprenaline induces in vivo myocyte necrosis in rat soleus muscle, and characterised the time-course, dose-response, spatial distribution and adrenoceptor involvement of its myotoxicity, in comparison with effects on cardiomyocytes in the same animals.


METHODS
Myocyte necrosis in response to subcutaneous isoprenaline was detected in vivo using a monoclonal anti-myosin antibody. Secondary immunoperoxidase staining (in vitro) facilitated the localisation of the damage and quantitative image analysis.


RESULTS
Using this sensitive technique we report a novel observation that isoprenaline induces significant myocyte necrosis (5-10%) in the soleus muscle. This toxic damage was initiated at lower doses of isoprenaline than in the myocardium (1 vs. 10 microg kg(-1) s.c.), and peaked earlier (at 12 vs. 18 h post injection). Damage was distributed throughout the soleus muscle, whereas cardiomyocyte necrosis was most marked in left ventricular subendocardium where it was approximately 10 and three times greater than in the subepicardium and atria, respectively. Using selective adrenoceptor (AR) antagonism, we found that isoprenaline myotoxicity was mediated via beta(2)-AR in the soleus and via beta(1)-AR in the myocardium.


CONCLUSIONS
The results show that the myopathic effects of isoprenaline are not confined to the heart. The involvement of skeletal muscle with different characteristics and mechanisms may have important implications in elucidating and treating the generalised myopathic processes seen in heart failure patients who have elevated levels of circulating catecholamines.
Ng
YeeLan
Y
Research Institute for Sport and Exercise Sciences, Liverpool John Moores University, 15-21 Webster Street, UK.
Goldspink
David F
DF
Burniston
Jatin G
JG
Clark
William A
WA
Colyer
John
J
Tan
Lip Bun
LB
D000818:Animals; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D007545:Isoproterenol / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity*; D008297:Male; D018657:Muscle Fibers, Slow-Twitch / Q000187:drug effects* / Q000473:pathology*; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000473:pathology*; D009336:Necrosis; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
D002316:Cardiotonic Agents; D007545:Isoproterenol