PMID- 35334826 OWN - NLM STAT- MEDLINE DCOM- 20220330 LR - 20220401 IS - 2072-6643 (Electronic) IS - 2072-6643 (Linking) VI - 14 IP - 6 DP - 2022 Mar 10 TI - 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. LID - 10.3390/nu14061166 [doi] LID - 1166 AB - 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 degrees 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. FAU - Giacco, Antonia AU - Giacco A AD - Dipartimento di Scienze e Tecnologie, Universita Degli Studi del Sannio, Via De Sanctis, 82100 Benevento, Italy. FAU - Cioffi, Federica AU - Cioffi F AD - Dipartimento di Scienze e Tecnologie, Universita Degli Studi del Sannio, Via De Sanctis, 82100 Benevento, Italy. FAU - Cuomo, Arianna AU - Cuomo A AD - Dipartimento di Scienze e Tecnologie Ambientali, Biologiche e Farmaceutiche, Universita Degli Studi Della Campania "Luigi Vanvitelli", Via Vivaldi 43, 81130 Caserta, Italy. FAU - Simiele, Roberta AU - Simiele R AD - Dipartimento di Scienze e Tecnologie Ambientali, Biologiche e Farmaceutiche, Universita Degli Studi Della Campania "Luigi Vanvitelli", Via Vivaldi 43, 81130 Caserta, Italy. FAU - Senese, Rosalba AU - Senese R AUID- ORCID: 0000-0003-1571-0980 AD - Dipartimento di Scienze e Tecnologie Ambientali, Biologiche e Farmaceutiche, Universita Degli Studi Della Campania "Luigi Vanvitelli", Via Vivaldi 43, 81130 Caserta, Italy. FAU - Silvestri, Elena AU - Silvestri E AD - Dipartimento di Scienze e Tecnologie, Universita Degli Studi del Sannio, Via De Sanctis, 82100 Benevento, Italy. FAU - Amoresano, Angela AU - Amoresano A AD - Dipartimento di Scienze Chimiche, Universita Degli Studi di Napoli "Federico II", Monte Sant'Angelo, Via Cinthia 4, 80126 Naples, Italy. AD - Istituto Nazionale Biostrutture e Biosistemi, Viale delle Medaglie d'Oro 305, 00136 Rome, Italy. FAU - Fontanarosa, Carolina AU - Fontanarosa C AD - Dipartimento di Scienze Chimiche, Universita Degli Studi di Napoli "Federico II", Monte Sant'Angelo, Via Cinthia 4, 80126 Naples, Italy. FAU - Petito, Giuseppe AU - Petito G AD - Dipartimento di Scienze e Tecnologie Ambientali, Biologiche e Farmaceutiche, Universita Degli Studi Della Campania "Luigi Vanvitelli", Via Vivaldi 43, 81130 Caserta, Italy. FAU - Moreno, Maria AU - Moreno M AD - Dipartimento di Scienze e Tecnologie, Universita Degli Studi del Sannio, Via De Sanctis, 82100 Benevento, Italy. FAU - Lanni, Antonia AU - Lanni A AD - Dipartimento di Scienze e Tecnologie Ambientali, Biologiche e Farmaceutiche, Universita Degli Studi Della Campania "Luigi Vanvitelli", Via Vivaldi 43, 81130 Caserta, Italy. FAU - Lombardi, Assunta AU - Lombardi A AD - Dipartimento di Biologia, Universita Degli Studi di Napoli "Federico II", Monte Sant'Angelo, Via Cinthia 4, 80126 Naples, Italy. FAU - de Lange, Pieter AU - de Lange P AUID- ORCID: 0000-0002-5256-3599 AD - Dipartimento di Scienze e Tecnologie Ambientali, Biologiche e Farmaceutiche, Universita Degli Studi Della Campania "Luigi Vanvitelli", Via Vivaldi 43, 81130 Caserta, Italy. LA - eng PT - Journal Article DEP - 20220310 PL - Switzerland TA - Nutrients JT - Nutrients JID - 101521595 RN - 0 (Amino Acids, Branched-Chain) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Thyroid Hormones) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - *Amino Acids, Branched-Chain MH - Animals MH - *Brain-Derived Neurotrophic Factor/metabolism MH - Chromatography, Liquid MH - Fasting MH - Male MH - Mammals/metabolism MH - Muscle, Skeletal/metabolism MH - Prefrontal Cortex/metabolism MH - Rats MH - Rats, Wistar MH - TOR Serine-Threonine Kinases/metabolism MH - Tandem Mass Spectrometry MH - Thyroid Hormones/metabolism PMC - PMC8952016 OTO - NOTNLM OT - fasting OT - mild endurance exercise OT - tissue BCAA OT - tissue BHB OT - tissue thyroid hormone (T3) COIS- The authors declare no conflict of interest. EDAT- 2022/03/27 06:00 MHDA- 2022/03/31 06:00 PMCR- 2022/03/10 CRDT- 2022/03/26 01:01 PHST- 2022/02/12 00:00 [received] PHST- 2022/03/04 00:00 [revised] PHST- 2022/03/08 00:00 [accepted] PHST- 2022/03/26 01:01 [entrez] PHST- 2022/03/27 06:00 [pubmed] PHST- 2022/03/31 06:00 [medline] PHST- 2022/03/10 00:00 [pmc-release] AID - nu14061166 [pii] AID - nutrients-14-01166 [pii] AID - 10.3390/nu14061166 [doi] PST - epublish SO - Nutrients. 2022 Mar 10;14(6):1166. doi: 10.3390/nu14061166.