Potential Vitamin E Signaling Mediators in Skeletal Muscle

Abstract

Vitamin E (Vit E) deficiency studies underline the relevance of this vitamin in skeletal muscle (SkM) homeostasis. The knowledge of the effectors and modulators of Vit E action in SkM cells is limited, especially in aging and chronic diseases characterized by a decline in musculoskeletal health. Vit E comprises eight fat-soluble compounds grouped into tocopherols and tocotrienols, which share the basic chemical structure but show different biological properties and potentials to prevent diseases. Vit E has antioxidant and non-antioxidant activities and both favorable and adverse effects depending on the specific conditions and tissues. In this review, we focus on the actual knowledge of Vit E forms in SkM functions and new potential signaling effectors (i.e., bioactive sphingolipids and myokines). The possible advantages of Vit E supplementation in counteracting SkM dysfunctions in sarcopenia and under microgravity will also be discussed.

Keywords: antioxidant action; microgravity; myokines; sarcopenia; skeletal muscle; sphingolipids; vitamin E.

Figure 1

(A) Stereochemical structures of tocotrienols and tocopherols. The four isoforms of both tocopherols and tocotrienols differ in the degree and position of methyl groups on the chromanol ring: the α-isomers are trimethylated, the β- and γ-isomers are dimethylated, and the δ-isomers are monomethylated. (B) Most relevant biological differences between tocotrienols and tocopherols.

Figure 2

Effects of tocopherols and tocotrienols on skeletal muscle. The figure shows the potential molecular mechanisms (blue arrows) by which tocopherols and tocotrienols act in SkM cells, leading to the modulation of biochemical processes (blue boxes) and tissue regeneration or atrophy. The double yellow arrows indicate an unknown relationship. Green arrow: decrease; red arrow: increase.

Figure 3

Sphingolipid structure, metabolism, and function in SkM. (A) The stereochemical structure of the sphingolipids sphingosine, ceramide, and sphingomyelin. (B) Balance between ceramide (Cer) and S1P content can affect the cellular fate. In SkM, S1P is a pro-survival and pro-myogenic factor, whereas ceramide inhibits myogenesis and promotes cell atrophy. (C) Sphingolipid metabolism. The de novo SL pathway occurs in the endoplasmic reticulum, where the condensation of serine and palmitoyl CoA by serine palmitoyltransferase (SPT) generates ceramide, which is then shuttled to the Golgi apparatus. Here, it is used as the building structure for the synthesis of sphingomyelin and other complex sphingolipids. Cer can also be generated by sphingomyelin hydrolysis catalyzed by sphingomyelinase (SMase) activity. Ceramide is then converted reversibly to sphingosine by ceramidase (CDase) or phosphorylated to ceramide-1-phosphate (C1P) by ceramide kinase (CERK) activity. Successively, sphingosine is phosphorylated by two isoforms of sphingosine kinases, SPHK1 and SPHK2, to S1P. The exit from the sphingolipid synthesis pathways occurs through S1P lyase, which promotes the degradation of S1P into hexadecenal and phosphoethanolamine. The latter is further metabolized into palmitoyl CoA. S1P is also a substrate of specific S1P phosphatases, which generate sphingosine. CERS: ceramide synthase; DEGS: sphingolipid delta 4-desaturases; SMS: sphingomyelin synthase; KDS: 3-ketodihydrosphingosine reductase. (D) S1P produced by the active membrane-bound SPHK from sphingosine (Sph) can be transported outside the cell by an ATP-binding cassette transporter named spinster homolog 2 (Spns2) and, acting as a ligand for specific GTP-binding protein-coupled receptors (S1PRs), can affect different signaling pathways. The orange boxes indicate the metabolites that are affected by Vit E.