Oxytocin/Osteocalcin/IL-6 and NGF/BDNF mRNA Levels in Response to Cold Stress Challenge in Mice: Possible Oxytonic Brain-Bone-Muscle-Interaction

Abstract

Oxytocin (Oxt), osteocalcin (Ost), and NGF/BDNF have a role in bone homeostasis, reproduction, and cognition. Oxt/Ost is required for muscle repair. We investigated gene response of muscle and the inter-organ communication following cold stress (CS). The mRNA quantity of Ngf, Ost, Oxt, Bdnf, p75ntr, Ntrk1, Gprc6a, Oxtr, Ntrk2, UCP1, and Il-6 genes in bone, brain, soleus (SOL), and tibialis anterior (TA) muscles from adult mice following CS were investigated. The myosin heavy-chain Mhc2b, Mhc1, Mhc2x, and Mhc2a gene expression were investigated. Mice were maintained at T = 23°C or 4°C for 6 h and 5-days (5d). CS mice did not show signs of muscle degeneration. An upregulation of Ucp1 and Ngf genes by 2 and 1.5 folds, respectively, in TA after 6 h CS and Ntrk1 by 4 and 22 folds in SOL muscle after 6 h and 5d CS, respectively, was observed; while after 6 h CS p75Ntr was downregulated in either muscle. Bdnf was unaffected, while after 5d CS Ntrk2 was upregulated in TA. Ost was downregulated in SOL by 0.9-folds at 5d. Following 5d CS, Oxtr and Il-6 genes were upregulated, respectively, by 1 and 1.5 folds in SOL. A downregulation of Mhc2b, respectively, by 0.96 and 0.88-folds after 6 h and 5d CS in SOL and Mhc2a was also downregulated by 0.88-fold after 5d CS in TA. Mhc1 and Mhc2x were not affected. Changes in the expression levels of genes in TA and SOL muscles, bone, and brain following CS were regulated by IL6 and Oxt. CS potentiates the slow-twitch phenotype of SOL which is in line with the metabolic need of this muscle, and the potentiation of the slow-twitch phenotype in TA. Oxt and IL6 coordinate a phenotype-dependent tonic effect of slow-twitch muscle and Oxt regulates the inter-organ interaction between brain and SOL muscle. Muscle tropism is maintained by NGF signaling following CS.

The New Frontier in Oxytocin Physiology: The Oxytonic Contraction

“…[54]. In our experiments, we found a potentiation of the slow-twitch muscle phenotype after CS [54], as shown by the downregulation of fast-twitch glycolytic myosin heavy-chain 2b (Mhc2b) and the increase of the ratio of myosin heavy chain 1 (slow-oxidative)/myosin heavy chain 2b (fast-twitch glycolytic) expression in soleus but not in TA [10] consistent with the metabolic need of the slow-twitch oxidative muscle after CS. Long-term CS for 5 d also induced a downregulation of Myhc2a in TA muscle living unaltered the slow-twitch Myhc1.…”

“…Conversely, the exogenous administration of Oxt drives skeletal muscle regeneration and increases muscle tone [24,30], and Oxt does not cross the blood brain barrier [45]. Then in a second set of experiments, we showed that skeletal muscle properties are influenced by Oxt and the cross-talk between hormones of skeletal muscle with bone and brain allows adaptation of these tissues to CS as previously shown [10,[51][52][53][54]. Skeletal muscle is also a source of heat production in cold-exposed humans and mice.…”

“…Consistent with these data, we hypothesized that Oxt may increase muscle tone to ensure a better response to the "fight response" and triggering "the oxytonic contraction." On this regard we showed that Oxtr expression increases in soleus muscle after cold stress challenge in mice [10]. The Oxt system is implicated also in the etiology of Prader-Willy syndrome, autistic spectrum disorder, and Schaaf-Yang syndrome [19].…”

“…This means that cold-stressed mice are in good health and regained their body weight. The enhancement of food intake following CS is linked to Oxt signaling in brain as this factor is involved in the regulation of food consumption [6,10]. For example, Oxt levels in plasma decreased in obese mice after high-fat diet but increased in synaptotagmin-4-deficient mice, which protects against diet-induced obesity [47].…”

“…These effects include the regulation of energy and metabolism, appetite regulation, and effects on the gastrointestinal system, skeletal, and cardiac muscle [9]. In this review, a special emphasis will be given to the effects of Oxt on skeletal muscle and to our recent paradigm shifting hypothesis that Oxt may increase the tone of the slow-twitch muscle upregulating its receptor and triggering the "oxytonic contraction" after cold stress challenge in mice [10,11].…”