S 1 P 3 receptor influences key physiological properties 1 of fast - twitch extensor digitorum longus muscle

26 27 To examine the role of sphingosine 1-phosphate (S1P) receptor 3 (S1P3) in modulating muscle 28 properties, we utilized transgenic mice depleted of the receptor. Morphological analyses of extensor 29 digitorum longus (EDL) muscle did not show evident differences between wild type and S1P3-null 30 mice. The body weight of three-month old S1P3-null mice and the mean cross sectional area of 31 transgenic EDL muscle fibers were similar to those of wild type. S1P3 deficiency enhanced the 32 expression level of S1P1 and S1P2 receptors mRNA in S1P3-null EDL muscle. The contractile 33 properties of S1P3-null EDL diverge from those of wild type, being largely more fatigable and less 34 able to recover. The absence of S1P3 appears responsible for a lower availability of calcium during 35 fatigue. S1P supplementation, expected to stimulate residual S1P receptors and signaling, reduced 36 fatigue development of S1P3-null muscle. Moreover, in the absence of S1P3, denervated EDL 37 atrophies less than wild type. The analysis of atrophy-related proteins in S1P3-null EDL evidences 38 high levels of the endogenous regulator of mitochondria biogenesis peroxisome proliferative 39 activated receptor-γ coactivator 1α (PGC-1α), that preserving mitochondria could protect the 40 muscle from disuse atrophy. In conclusion, the absence of S1P3 makes the muscle more sensitive to 41 fatigue and slows down atrophy development after denervation, indicating that S1P3 is involved in 42 the modulation of key physiological properties of the fast-twitch EDL muscle. 43 44 45