S1P3 receptor influences key physiological properties of fast-twitch extensor digitorum longus muscle

To examine the role of sphingosine 1-phosphate (S1P) receptor 3 (S1P(3)) in modulating muscle properties, we utilized transgenic mice depleted of the receptor. Morphological analyses of extensor digitorum longus (EDL) muscle did not show evident differences between wild-type and S1P(3)-null mice. The body weight of 3-mo-old S1P(3)-null mice and the mean cross-sectional area of transgenic EDL muscle fibers were similar to those of wild-type. S1P(3) deficiency enhanced the expression level of S1P(1) and S1P(2) receptors mRNA in S1P(3)-null EDL muscle. The contractile properties of S1P3-null EDL diverge from those of wild-type, largely more fatigable and less able to recover. The absence of S1P(3) appears responsible for a lower availability of calcium during fatigue. S1P supplementation, expected to stimulate residual S1P receptors and signaling, reduced fatigue development of S1P(3)-null muscle. Moreover, in the absence of S1P(3), denervated EDL atrophies less than wild-type. The analysis of atrophy-related proteins in S1P(3)-null EDL evidences high levels of the endogenous regulator of mitochondria biogenesis peroxisome proliferative-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha); preserving mitochondria could protect the muscle from disuse atrophy. In conclusion, the absence of S1P(3) makes the muscle more sensitive to fatigue and slows down atrophy development after denervation, indicating that S1P(3) is involved in the modulation of key physiological properties of the fast-twitch EDL muscle.