Mild Endurance Exercise during Fasting Increases Gastrocnemius Muscle and Prefrontal Cortex Thyroid Hormone Levels through Differential BHB and BCAA-Mediated BDNF-mTOR Signaling in Rats.

Antonia Giacco,Elena Silvestri,Angela Amoresano,Carolina Fontanarosa,Giuseppe Petito,Federica Cioffi,Maria Moreno,Pieter De Lange,Antonia Lanni,Rosalba Senese,Arianna Cuomo,Assunta Lombardi,Roberta Simiele

doi:10.3390/nu14061166

Abstract

Mild endurance exercise has been shown to compensate for declined muscle quality and may positively affect the brain under conditions of energy restriction. Whether this involves brain-derived neurotrophic factor (BDNF) and mammalian target of rapamycin (mTOR) activation in relation to central and peripheral tissue levels of associated factors such as beta hydroxy butyrate (BHB), branched-chain amino acids (BCAA) and thyroid hormone (T3) has not been studied. Thus, a subset of male Wistar rats housed at thermoneutrality that were fed or fasted was submitted to 30-min-mild treadmill exercise bouts (five in total, twice daily, 15 m/min, 0° inclination) over a period of 66 h. Prefrontal cortex and gastrocnemius muscle BHB, BCAA, and thyroid hormone were measured by LC-MS/MS analysis and were related to BDNF and mammalian target of rapamycin (mTOR) signaling. In gastrocnemius muscle, mild endurance exercise during fasting maintained the fasting-induced elevated BHB levels and BDNF-CREB activity and unlocked the downstream Akt-mTORC1 pathway associated with increased tissue BCAA. Consequently, deiodinase 3 mRNA levels decreased whereas increased phosphorylation of the mTORC2 target FOXO1 was associated with increased deiodinase 2 mRNA levels, accounting for the increased T3 tissue levels. These events were related to increased expression of CREB and T3 target genes beneficial for muscle quality previously observed in this condition. In rat L6 myoblasts, BHB directly induced BDNF transcription and maturation. Mild endurance exercise during fasting did not increase prefrontal cortex BHB levels nor was BDNF activated, whereas increased leucine levels were associated with Akt-independent increased phosphorylation of the mTORC1 target P70S6K. The associated increased T3 levels modulated the expression of known T3-target genes involved in brain tissue maintenance. Our observation that mild endurance exercise modulates BDNF, mTOR and T3 during fasting provides molecular clues to explain the observed beneficial effects of mild endurance exercise in settings of energy restriction.

Highlights

Weight loss by nutritional interventions often leads to muscle weakness [1]
We first investigated whether beta hydroxy butyrate (BHB) and branched-chain amino acids (BCAA) are involved in the response to mild endurance exercise during fasting in gastrocnemius muscle, and how this could be related to brainderived neurotrophic factor (BDNF)-mammalian target of rapamycin (mTOR) signaling
Fasting-related increased gastrocnemius muscle BDNF signaling can be functionally coupled to the chronic increase in gastrocnemius muscle levels of BHB since we observed that this compound directly stimulates BDNF activation in rat L6 myoblasts, in analogy to what has been described in cortical neurons [32]

Summary

Introduction

In studies focusing on evaluating optimal weight-loss strategies, mild endurance exercise has emerged to be sufficient to counteract the negative impact of various energy-restricting nutritional interventions on muscle strength and quality in obese and non-obese subjects (see, for review, [1]), and in rodents alternate fasting and exercise has likewise been shown to improve endurance performance [2]. In this light, at the biochemical level there exists evidence for a compensatory role for exercise on fasting-mediated protein breakdown linked to insulin-independent reactivation of Akt/mammalian target of rapamycin (mTOR) C1 signaling in mice [3] and humans [4], which would impact muscle mass and quality. BDNF has been shown to induce mammalian target of rapamycin (mTOR)C1 activity in response to energetic challenges in the cortex, with beneficial effects for cognition [11]

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Conclusion