Heart failure increases neutral sphingomyelinase activity and ceramide content in rat diaphragm

Patients with chronic heart failure (CHF) have skeletal muscle weakness and elevated secretory sphingomyelinase activity. Sphingomyelinase (SMase) acts through ceramide to depress skeletal muscle force in vitro . We hypothesized that diaphragm weakness in CHF is accompanied by increases in SMase activity and tissue ceramide content. We studied rats 14–16 weeks after myocardial infarction (n = 5–10) and sham surgery (n = 10–13). CHF was confirmed by a decrease in left‐ventricular fractional shortening measured by echocardiography (Sham 38 ± 2%, CHF 28 ± 1%; P < 0.05). Skeletal muscle dysfunction in CHF was confirmed by decreased maximal tetanic force of diaphragm strips (in N/cm 2 : Sham 30 ± 0.6, CHF 26 ± 0.5; P < 0.05). CHF elicited a 27% increase ( P < 0.05) in neutral SMase (N‐SMase) activity. Consistent with this finding, total ceramide content was elevated in CHF diaphragm (in pmol/mg protein: Sham, 280 ± 5 and CHF, 343 ± 16; P < 0.05)—subspecies heightened ( P < 0.05) in CHF were C 18 , C 18:1 , C 20 , C 20:1 , C 20:4 , C 22:1 . Acid SMase activity was unchanged in CHF. Similarly, there were no changes in the content of either sphingosine or sphingosine‐1‐phosphate ( P > 0.05). Our data suggests that increased diaphragm ceramide content is a consequence of N‐SMase activation in CHF. Activation of N‐SMase and heightening of ceramide content may contribute to skeletal muscle weakness. Funding support: NIH 1K99HL098453‐01, 4R00HL098453‐02