Ablation of S1P₃ receptor protects mouse soleus from age-related drop in muscle mass, force, and regenerative capacity

Abstract

We investigated the effects of S1P deficiency on the age-related atrophy, decline in force, and regenerative capacity of soleus muscle from 23-mo-old male (old) mice. Compared with muscle from 5-mo-old (adult) mice, soleus mass and muscle fiber cross-sectional area (CSA) in old wild-type mice were reduced by ~26% and 24%, respectively. By contrast, the mass and fiber CSA of soleus muscle in old S1P-null mice were comparable to those of adult muscle. Moreover, in soleus muscle of wild-type mice, twitch and tetanic tensions diminished from adulthood to old age. A slowing of contractile properties was also observed in soleus from old wild-type mice. In S1P-null mice, neither force nor the contractile properties of soleus changed during aging. We also evaluated the regenerative capacity of soleus in old S1P-null mice by stimulating muscle regeneration through myotoxic injury. After 10 days of regeneration, the mean fiber CSA of soleus in old wild-type mice was significantly smaller (-28%) compared with that of regenerated muscle in adult mice. On the contrary, the mean fiber CSA of regenerated soleus in old S1P-null mice was similar to that of muscle in adult mice. We conclude that in the absence of S1P, soleus muscle is protected from the decrease in muscle mass and force, and the attenuation of regenerative capacity, all of which are typical characteristics of aging.

Control of Skeletal Muscle Atrophy Associated to Cancer or Corticosteroids by Ceramide Kinase

“…Our group, and others, contributed to clarify the role of the bioactive S1P in SkM cell biology, showing its role as pro-survival and myogenic factor [13,[51][52][53][54]. The capability of S1P to also modulate SkM phenotype has been also documented in vivo and ex-vivo/in vitro by our group and others [17,26,55]. Compared with SphK, the information regarding the involvement of CerK and its product C1P in SkM phenotype is limited.…”

Reduction of circulating sphingosine‐1‐phosphate worsens mdx soleus muscle dystrophic phenotype

“…Therefore, the increased level of the two atrophy‐specific E3 ubiquitin ligases, atrogin‐1 and MuRF1, and of the autophagic marker, p62, and the LC3II/I ratio indicate that S1P deprivation induces activation of the atrophy/autophagy process and explains the reduced mean fibre CSA of the antibody‐treated mdx soleus. It is possible that S1P might exert its trophic effects directly on the muscle and/or indirectly through the neuromuscular junction (Bondì et al., 2017; Zanin et al., 2008).…”

“…Soleus muscle regeneration was induced by notexin as previously published (Bondì et al., 2017). Acute degeneration was induced in the left soleus by injecting, through a small cutaneous incision, 0.075 ml of the myotoxic drug notexin (0.5%; Sigma, St Louis, MO, USA).…”

“…Both S1P 1 and S1P 3 receptors are expressed in adult muscle fibres, possibly to mediate the trophic action of S1P (Ieronimakis et al., 2013; Zanin et al., 2008). The S1P 3 isoform was shown to affect key physiological functions of the mouse extensor digitorum longus muscle (Germinario et al., 2016) and to control age‐related changes of the soleus muscle (Bondì et al., 2017). S1P 1 is also expressed at the neuromuscular junction (Zanin et al., 2008).…”

S1P/S1P Receptor Signaling in Neuromuscolar Disorders

“…In addition, Bondì et al [128] observed that S1P/S1PR3 axis plays a negative role in muscle mass maintenance and force in soleus during aging and extracellular S1P exerts a protective effect during muscle fatigue development [129]. S1P/S1PR3 signaling also modulates excitation-contraction coupling and intracellular calcium mobilization [121][122][123][124][125][126][127][128][129][130].…”