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Review
, 15 (9), 2501-17

Sphingolipid Metabolism, Oxidant Signaling, and Contractile Function of Skeletal Muscle

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Review

Sphingolipid Metabolism, Oxidant Signaling, and Contractile Function of Skeletal Muscle

Mariana N Nikolova-Karakashian et al. Antioxid Redox Signal.

Abstract

Significance: Sphingolipids are a class of bioactive lipids that regulate diverse cell functions. Ceramide, sphingosine, and sphingosine-1-phosphate accumulate in tissues such as liver, brain, and lung under conditions of cellular stress, including oxidative stress. The activity of some sphingolipid metabolizing enzymes, chiefly the sphingomyelinases, is stimulated during inflammation and in response to oxidative stress. Ceramide, the sphingomyelinase product, as well as the ceramide metabolite, sphingosine-1-phosphate, can induce the generation of more reactive oxygen species, propagating further inflammation.

Recent advances: This review article summarizes information on sphingolipid biochemistry and signaling pertinent to skeletal muscle and describes the potential influence of sphingolipids on contractile function.

Critical issues: It encompasses topics related to (1) the pathways for complex sphingolipid biosynthesis and degradation, emphasizing sphingolipid regulation in various muscle fiber types and subcellular compartments; (2) the emerging evidence that implicates ceramide, sphingosine, and sphingosine-1-phosphate as regulators of muscle oxidant activity, and (3) sphingolipid effects on contractile function and fatigue.

Future directions: We propose that prolonged inflammatory conditions alter ceramide, sphingosine, and sphingosine-1-phosphate levels in skeletal muscle and that these changes promote the weakness, premature fatigue, and cachexia that plague individuals with heart failure, cancer, diabetes, and other chronic inflammatory diseases.

Figures

FIG. 1.
FIG. 1.
Chemical structures of major sphingolipid metabolites. Diagrams illustrate structures of three commonly studied metabolites.
FIG. 2.
FIG. 2.
Metabolism of sphingolipids in mammalian cells. SPT, Serine palmitoyltransferase; CERS, (dihydro)ceramide synthase; dihydroceramide desaturase; CERT, ceramide transfer protein; SMS, sphingomyelin synthase; CERK, ceramide kinase; CPP, ceramide-1-phosphate phosphatase; nSMase1, nSMase2, aSMase, sphingomyelinase; ASAH1,2, ACER, ceramidase; SK, sphingosine kinase; SPL, sphingosine phosphate lyase; SPP, sphingosine phosphate phosphatase.
FIG. 3.
FIG. 3.
Cellular responses to sphingolipid metabolites. Summary of biological activities reported for major sphingolipid mediators in muscle versus nonmuscle cell types.
FIG. 4.
FIG. 4.
Actions of sphingolipids on mitochondrial reactive oxygen species (ROS) production. Upper panel: electron micrograph of sarcomere from murine soleus muscle. Middle. Expanded image of intermyofibrillar mitochondrion apposed to a sarcoplasmic reticulum (SR) terminal cisternae/t-tubule junction. Lower panel: Diagram depicts mechanisms by which sphingolipids are proposed to act on the electron transport system (ceramide) and on calcium regulation (sphingosine, sphingosine-1-phosphate) to alter mitochondrial ROS production; see text for explanation.
FIG. 5.
FIG. 5.
Sphingolipid effects on muscle fatigue. Upper panel: relative forces (% initial force at time 0) developed by murine extensor digitorum longus muscles in oxygenated buffer containing 5 μM bovine serum albumin (control; open symbols) or 10 μM sphingosine (SPH, closed symbols); muscles were studied at 30°C using repetitive, maximal tetanic stimuli (150 Hz, 200 ms trains, 0.2 trains/s); sphingosine increased relative force during fatigue and recovery; n=4/group; *p<0.05 versus time-matched control; reproduced with permission from (26). Lower panel: specific force (N/cm2) of fiber bundles from murine diaphragm in oxygenated buffer (dashed line), buffer containing recombinant bacterial SMase 0.5 U/ml (closed squares), or buffer containing SMase plus N-acetylcysteine 10 mM (NAC, shaded squares) at 37°C during submaximal tetanic stimulation using a matched-force protocol (40–71 Hz, 500 ms trains, 0. 5 trains/s); SMase promoted fatigue, an effect abolished by NAC; n=5–7/group; *p<0.05 control versus SMase; φp<0.05 SMase versus SMase+NAC; reproduced with permission from Ferreira et al. (38).
FIG. 6.
FIG. 6.
Sphingolipids as mediators of muscle dysfunction. Global model depicts events by which sphingolipid metabolites may promote weakness and fatigue caused by chronic inflammatory disease or environmental stress; model integrates data from published reports as detailed in text.

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