EDITORIAL FOCUSA novel role for sphingolipid metabolism in oxidant-mediated skeletal muscle fatigue. Focus on “Sphingomyelinase stimulates oxidant signaling to weaken skeletal muscle and promote fatigue”L. Ashley CowartL. Ashley CowartBiochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina, and the Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South CarolinaPublished Online:01 Sep 2010https://doi.org/10.1152/ajpcell.00236.2010This is the final version - click for previous versionMoreSectionsPDF (134 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInEmailWeChat sphingolipids are a chemically diverse group of biological lipids typified by a sphingoid base backbone derived from condensation of a fatty acyl-CoA to an amino acid (typically, but not always, serine) (24, 27). These lipids occur throughout eukaryotic species, thus reflecting their fundamental significance in cell biology. A series of studies in the late 1980s by Hannun, Bell, Merrill, and others demonstrated that sphingolipids inhibited protein kinase C, a finding that elevated the appreciation of this lipid class from relatively inert membrane constituents to molecules that participate in signaling and cell regulation (10–13, 21, 22). Efforts directed toward dissecting sphingolipid metabolism and functions in subsequent years revealed a complex and dynamic cellular metabolic network regulated in response to external signals including hormones, cytokines, nutrient deprivation, thermal stress, irradiation, chemotherapeutic agents, and many other stimuli (for review, see Refs. 14 and 18).The sphingolipid at the hub of this network, ceramide, has served as a major research focus for over 20 years in part due to its participation in stress-induced signaling pathways. While a major research thrust has been directed toward the roles of this lipid in apoptosis, senescence, and stress responses, especially with respect to cancer and its treatment, more recent research has addressed roles for ceramide in other pathophysiological processes including aging, metabolic disease including obesity, diabetes, and the metabolic syndrome, heart failure, inflammation, and many others. The article by Ferreira et al. (8) adds to the growing list of roles for ceramide by demonstrating that treatment of skeletal muscle with a sphingomyelinase enzyme, which generates ceramide at the plasma membrane, decreased contractile force in diaphragm slices in vitro and promoted muscle fatigue.The experimental strategy used for this work, i.e., treating cells or tissue with a soluble prokaryotic sphingomyelinase, is analogous to the in vivo situation of endogenous secreted sphingomyelinase (S-SMase). Several sphingomyelinase isoforms occur in mammals, including two neutral sphingomyelinase isoforms (nSMases 2 and 3), and a lysosomal acid sphingomyelinase (aSMase), responsible for the lipid storage disorder Niemann-Pick disease and encoded by the SMPD1 gene (17). The S-SMase is an alternatively trafficked version of the lysosomal enzyme that undergoes modifications promoting its secretion in response to inflammatory stimuli. Although S-SMase increases in diabetes, heart failure, sepsis, and other proinflammatory conditions, specific functions for S-SMase remain to be determined. The authors speculate that S-SMase may cause the muscle weakening observed in patients suffering from chronic heart failure. Indeed, this novel role of S-SMase in muscle weakening may have broader implications to other conditions that increase inflammation or S-SMase.These authors contribute to a small but growing body of work placing ceramide upstream, rather than downstream, of oxidative stress. The standard paradigm, which gains support from many years of research, holds that stressors including reactive oxygen species (ROS) activate some sphingomyelinase isoforms to generate ceramide (1, 19, 26). However, in this study (and several other recent works as cited by the authors), muscle weakening in response to bacterial sphingomyelinase treatment was ameliorated by treatment with the antioxidant N-acetylcysteine, indicating a potential role for ceramide-mediated oxidant signaling in promoting muscle weakness. Moreover, both bacterial sphingomyelinase treatment and addition of exogenous ceramides significantly increased cellular oxidant activity, and specificity was demonstrated in that attenuation of reactive nitrogen species had no inhibitory effect. Placing ceramide upstream of ROS generation presents an opportunity for a feed-forward regulatory loop, such that sphingomyelinase-mediated ceramide production at the plasma membrane, as occurs with bacterial SMase treatment and presumably increases in vivo when S-SMase is increased, generates ROS, which might activate intracellular neutral sphingomyelinase (nSMase). Intriguingly, nSMase generates primarily ceramides with 16- and 24-carbon N-acyl chains, which are the major species that increased with bacterial SMase treatment in the current study (5, 6, 23). While this does not rule out a direct contribution to changes in ceramides from the bacterial SMAse, it bears mention that activation of nSMase by oxidant signaling could also contribute to the observed ceramide increase.Another major contribution of this work to our current knowledge is that, though sphingolipids play many roles in skeletal muscle, a role in pathological muscle weakness is a new finding. Work from the laboratory of Dr. Paula Bruni and her affiliates has demonstrated a key role for sphingosine-1-phosphate in myoblast differentiation, in development as well as in skeletal muscle repair; these and other studies also implicate this lipid in muscle contraction and protection from fatigue (for review, see Ref. 3). On the other hand, ceramide is implicated in depression of myogenic differentiation (20), inhibition of protein synthesis in response to cytokines (16), and insulin resistance in animal models and/or skeletal muscle model systems (4, 25). Ceramide also decreased in response to prolonged exercise in rat and human muscle (2, 7, 15). Thus, the current study establishes a role for sphingolipid metabolism in muscle fatigue, and, moreover, specifically implicates SMase activity at the plasma membrane in this process. Moreover, a recurring concept in sphingolipid research is that the opposite actions of sphingosine-1-phosphate and ceramide (for example, mitogenesis vs. senescence, respectively) can be viewed as a “rheostat” (9); thus, these two lipids, with opposing roles in muscle fatigue, may extend this relationship to skeletal muscle weakness.The work raises several important questions. First, the authors used a well-established model system for secreted sphingomyelinase, bacterial SMase. While in vivo extracellular S-SMase represents an alternatively trafficked form of acid sphingomyelinase encoded by the SMPD1 gene, many groups have used soluble bacterial isoforms derived from Staphylococcus aureus or Bacillus cereus, which are readily available from commercial sources. Would endogenous S-SMase induce these same effects? Moreover, several pathways of ceramide generation exist within the cell, including de novo biosynthesis, which also can increase in inflammatory conditions. These pathways may generate ceramide at distinct intracellular locations (Fig. 1). Thus, could other pathways also induce muscle weakness, or is it necessarily production in the outer leaflet of the plasma membrane that would generate oxidant stress and subsequent muscle weakness and fatigue? Similarly in other physiological conditions that weaken muscle and/or increase systemic inflammation, for example, obesity, diabetes, and sarcopenia, could S-SMase also play a role? These and other important questions should be the subject of further work in this area; these findings may present novel opportunities for improving patient health and well being through targeting sphingolipid metabolic pathways.Fig. 1.Cellular pathways and localization of ceramide production. Ceramide is synthesized de novo from serine and acyl-CoA on the cytoplasmic surface of the endoplasmic reticulum. Synthesis of sphingomyelin from ceramide occurs in the Golgi (on the exoplasmic leaflet). 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Ceramides and other bioactive sphingolipid backbones in health and disease: lipidomic analysis, metabolism and roles in membrane structure, dynamics, signaling and autophagy. Biochim Biophys Acta 1758: 1864–1884, 2006.Crossref | PubMed | ISI | Google ScholarAUTHOR NOTESAddress for reprint requests and other correspondence: L. Ashley Cowart, Dept. of Biochemistry and Molecular Biology, Medical Univ. of South Carolina, Charleston, SC 29425 (e-mail: [email protected]edu). 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