Apoptosis in the skeletal muscle of rats with heart failure is associated with increased serum levels of TNF-alpha and sphingosine.
Skeletal muscle in congestive heart failure (CHF) is responsible for increased fatigability, decreased endurance and exercise capacity. A specific myopathy with increased expression of fast myosin heavy chains (MHCs), myocyte atrophy, secondary to myocyte apoptosis, that is triggered by high levels of circulating tumor necrosis factor (TNF-alpha) has been described. However, a direct effect of TNF-alpha on skeletal muscle has not been described yet. In this paper we put forward the hypothesis that TNF-alpha plays an indirect effect on skeletal myocytes. In an animal model of CHF, the monocrotaline-treated rat, we have observed a significant (P<0.001) increase of circulating TNF-alpha that is paralleled by increased serum levels of the endogenous second messenger, sphingosine (SPH), (from 0.71+/-0.15 to 1.32+/-0.39 nmoles/ml, P<0.01). In the tibialis anterior (TA) muscle we found a marked increase of myocyte apoptosis (from 1.4+/-2.4 to 40.1+/-39.5 nuclei/mm(3), P<0.04). We correlated plasma levels of TNF-alpha with those of SPH and in turn with the magnitude of apoptosis. Linear regression showed a significant correlation between TNF-alpha, SPH, and apoptosis (r(2)=0.74, P=0.004 and r(2)=0.87, P=0.001 respectively). Analysis of covariance showed that TNF-alpha and SPH were independently correlated with the number of apoptotic nuclei (P=0.0001). In parallel in vitro experiments, where increasing concentrations of SPH were applied to skeletal muscle cells in culture, we observed a dose-dependent increase in apoptosis. These results suggest that TNF-alpha-induced SPH production may be responsible for skeletal muscle apoptosis. The link between TNF-alpha and skeletal muscle apoptosis could be represented by the second messenger SPH, which can directly induce apoptosis in these cells.
Dalla Libera
L
L
CNR Unit for Muscle Physiopathology, University of Padova, Padova, Italy. ldl@civ.bio.unipd.it
Sabbadini
R
R
Renken
C
C
Ravara
B
B
Sandri
M
M
Betto
R
R
Angelini
A
A
Vescovo
G
G
D000804:Angiotensin II / Q000096:biosynthesis; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D006333:Heart Failure / Q000378:metabolism*; D006352:Heart Ventricles / Q000473:pathology; D017380:Hypertrophy, Right Ventricular / Q000473:pathology; D020287:In Situ Nick-End Labeling; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013110:Sphingosine / Q000097:blood / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D014409:Tumor Necrosis Factor-alpha; D000804:Angiotensin II; D013110:Sphingosine