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Review
. 2020 Aug 7:11:491.
doi: 10.3389/fendo.2020.00491. eCollection 2020.

Sphingolipid Metabolism and Signaling in Skeletal Muscle: From Physiology to Physiopathology

Sophie Tan-Chen  1   2 , Jeanne Guitton  3 , Olivier Bourron  1   2   4 , Hervé Le Stunff  3 , Eric Hajduch  1   2
Affiliations
Review

Sphingolipid Metabolism and Signaling in Skeletal Muscle: From Physiology to Physiopathology

Sophie Tan-Chen et al. Front Endocrinol (Lausanne). .

Abstract

Sphingolipids represent one of the major classes of eukaryotic lipids. They play an essential structural role, especially in cell membranes where they also possess signaling properties and are capable of modulating multiple cell functions, such as apoptosis, cell proliferation, differentiation, and inflammation. Many sphingolipid derivatives, such as ceramide, sphingosine-1-phosphate, and ganglioside, have been shown to play many crucial roles in muscle under physiological and pathological conditions. This review will summarize our knowledge of sphingolipids and their effects on muscle fate, highlighting the role of this class of lipids in modulating muscle cell differentiation, regeneration, aging, response to insulin, and contraction. We show that modulating sphingolipid metabolism may be a novel and interesting way for preventing and/or treating several muscle-related diseases.

Keywords: ceramide; diabetes; glycosphingolipids; insulin; obesity; sphingomyelin; sphingosine-1-phosphate.

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Figures

Figure 1
Figure 1
Metabolism of sphingolipids. SLs can be synthetized through three major metabolic pathways: the de-novo pathway coming from the condensation of SFA (palmitate) with serine, the salvage pathway and the SMase pathway. ER, endoplasmic reticulum; SPT, serine palmitoyl transferase; KDSR, 3-keto-dihydrosphingosine; CerS, ceramide synthase; DES, dihydroceramide desaturase; GBA, acid β-glucosidase; SMase, sphingomyelinase; CDase, ceramidase; SMase, sphingomyelinase; SMS, sphingomyelin synthase; CerK, ceramide kinase; GCS, glucosyl ceramide synthase; SphK, sphingosine kinase; SPP, lipid sphingosine phosphatase; SPL, sphingosine-1-phosphate lyase.
Figure 2
Figure 2
Divergent roles of sphingosine-1-phosphate and ceramide in skeletal muscle cell fate. (A) Schematic representation of S1PR signaling activation in muscle differentiation. (B) The “ceramide / sphingosine-1-phosphate rheostat” model emphasizes antagonistic roles of ceramide and S1P in the regulation of myogenesis and glucose metabolism.
Figure 3
Figure 3
Mechanisms of action of ceramide on insulin signaling and glucose metabolism in muscle cells. (A) Palmitate induces the de-novo production of several ceramide species in muscle cells. Ceramide inhibits the muscle insulin signaling pathway and muscle metabolism by targeting two important actors, Akt and IRS1. Ceramide rapidly activates either PP2A or PKCζ to inactivate Akt. Ceramides also induce PKR/JNK and/or Prep1/p160 axes to target IRS1. IRS1, Insulin receptor substrate 1; JNK, c-Jun NH2-terminal kinase; PI3K, Phosphoinositide-3-kinase; PKCζ, Protein kinase C ζ; PKR, Double stranded ARN-activated protein kinase; PP2A, Protein phosphatase 2A; Prep1, Pbx regulating protein 1; P, phosphorylation. (B) Proposed model of muscle ceramide action on regulating whole-body glucose metabolism. Obesity-induced lipid overflow in muscle induces an increase in CerS1 expression and C18-ceramide content which decrease in Fgf21 production and secretion from muscle cells. This lack of Fgf21 secretion could affect the ability of insulin to suppress hepatic glucose production and will induce hyperglycemia.
Figure 4
Figure 4
Effects of ceramide metabolite accumulation on insulin signaling. Whole-tissue accumulation of ceramide-1-phosphate and glucosylceramide damages insulin sensitivity without significant action in muscle glucose metabolism. In opposite, accumulation of SM prevents ceramide buildup and improves insulin sensitivity in muscle cells. The SphK1/S1P/S1PR axis displays controversial actions on insulin sensitivity but activates glucose uptake in muscle cells.
Figure 5
Figure 5
Effect of exercise on ceramide accumulation and muscle energy requirements. (A) In sedentary lean people, acute exercise induces a transient increase in ceramide synthesis that momentarily blocks the anti-lipolytic action of insulin and therefore favors FA production and energy needs through β-oxidation. (B) Chronic exercise promotes increased entry of FA into muscle cells and their oxidation to fulfill the energy need, without any ceramide production. (C) In obese patients practicing physical activity, large intracellular FA concentrations are deflected toward β-oxidation for energy purposes, thereby reducing muscle ceramide synthesis flux and concentrations.
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