Oxtr/TRPV1 expression and acclimation of skeletal muscle to cold-stress in male mice

Abstract

We explored the involvement of Oxytocin receptor (Oxtr)/ Transient-receptor-potential-vanilloid-1 (TRPV1) genes and Oxytocin (Oxt) on the adaptation of skeletal muscle to cold stress challenge in mice. Oxtr expression in hypothalamic paraventricular (PVN), supraoptic nuclei (SON), and hippocampus (HIPP) were evaluated by immunohistochemistry in parallel with the measurement of circulating Oxt. The Oxtr and TRPV1 gene expression in Soleus (SOL) and Tibialis Anterior (TA) muscles were investigated by RT-PCR. Histological studies of the cardiac muscle after cold stress were also performed. Male mice (n=15) were divided into controls maintained at room temperature (RT=24°C), exposed to cold stress (CS) at T=4°C for 6 hours (6h), and 5 days (5d). Immunohistochemical studies showed that Oxtr protein expression increased by 2-fold (p=0.01) in PVN and by 1.5-fold (p=0.0001) in HIPP after 6h and 5d CS, but decreased by 2-fold (p=0.026) in SON at 5d. Both Oxtr and TRPV1 gene expression increased after 6h and 5d CS in SOL and TA muscles. Oxtr vs TRPV1 gene expression in SOL and TA muscles evaluated by regression analysis was linearly correlated following CS at 6h and 5d but not at control temperature of 24+1°C, supporting the hypothesis of coupling between these genes. The circulating levels of Oxt are unaffected after 6h CS but decreased by 0.2-fold (p=0.0141) after 5d CS. This is the first report that Oxtr and TRPV1 expression are upregulated in response to cold acclimation in skeletal muscle. The up-regulation of Oxtr in PVN and HIPP balances the decrease of circulating Oxt.

Oxytocin Involvement in Body Composition Unveils the True Identity of Oxytocin

“…Echinotocin causes contraction of in vitro preparations of the esophagus and tube feet in sea urchins [30]. This effect of echinotocin as a muscle contractant is consistent with the myoexcitatory effects of VP/Oxt type neuropeptides in many other taxa and with our theory [19,40]. In vertebrates, VP/Oxt-type neuropeptides are mostly known for their effects on reproductive physiology/behavior, feeding and digestive process and osmoregulation [41,42] and Oxt inhibits feeding [43,44] in mammals.…”

“…This concept was named in our laboratory as "The oxytocin paradox". This discrepancy can be explained by the fact that Oxt may only mark the identity of neurons projecting from Paraventricular nucleus of the hypothalamus (PVN) but its action is mediated by classical neurotransmitters like GABA, alternatively, Oxt may be anorexigenic in normal mice, but compensatory mechanisms may take place in Oxt −/− or Oxtr −/− mice [17][18][19]. Another hypothesis was that the appetite of Oxt −/− reported as normal, in spite of the hyperleptinemia, was excessive relative to the degree of adiposity [20].…”

“…Oxt signaling is important for whole-body glucose metabolism and Oxt administration in humans reducing fasting respiratory quotient meaning that Oxt can induce a shift from carbohydrate to fat oxidation [21,22]. Recently, and about 10 years after these first discoveries, three different studies have been published by Yuan et al [23], Sun et al [24], Conte et al [19], each of them presenting a different theory on the role of Oxt in the regulation of energy metabolism and the paradox of normophagic obesity that we first described for Oxt −/− and Oxtr −/− mice [15,16]. Specifically, in Yuan et al [23], the author analyzed the role of Oxt in energy homeostasis after a cold stress (CS) challenge and found that Oxt dissipates stored energy in brown adipose tissue (BAT) and white adipose tissue (WAT) improving metabolic dysfunctions in obese mice.…”

“…Moreover, they found that Oxt reduces body fat and reduces white to brown transition, probably as a compensatory mechanism to conserve energy after the loss of body weight. Lastly, in the study of Conte et al [19], the author analyzed the involvement of Oxtr/Transient-receptor-potential-vanilloid-1 (TRPV1) genes in the adaptation of skeletal muscle to CS in mice and found that Oxtr increases in hypothalamus. Circulating Oxt decreases after CS following a negative feedback loop in the brain.…”

“…In this review, we described and compared these three theories by Yuan et al [23], Sun et al [24], and Conte et al [19] on the role of Oxt in body composition and outside of pregnancy with the intent of incorporating them into one complete theory.…”