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

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.

Is Brain-Derived Neurotrophic Factor a Metabolic Hormone in Peripheral Tissues?

“…At the molecular level, metabolic flexibility relies on the configuration of signaling pathways that manage nutrient sensing, uptake, transport, storage, and utilization. In cultured C2C12 myotubes, BDNF secretion was provoked by the biochemical factors of fasting, including glucose depletion, amino acid restriction, and β-hydroxybutyrate (βHB) stimulation [ 28 , 60 , 80 , 81 ]. We and others have also shown that Bdnf expression in Skm is increased during fasting, suggesting mBDNF might be involved in regulating metabolism to move through the fed-fast cycle [ 60 , 81 ].…”

“…In cultured C2C12 myotubes, BDNF secretion was provoked by the biochemical factors of fasting, including glucose depletion, amino acid restriction, and β-hydroxybutyrate (βHB) stimulation [ 28 , 60 , 80 , 81 ]. We and others have also shown that Bdnf expression in Skm is increased during fasting, suggesting mBDNF might be involved in regulating metabolism to move through the fed-fast cycle [ 60 , 81 ]. Giacco et al further demonstrated that fasting-induced Bdnf expression is associated with elevated phosphorylation of cAMP-responsive element-binding protein (CREB), TrkB, and AMPK in the skeletal muscle [ 81 ].…”

“…We and others have also shown that Bdnf expression in Skm is increased during fasting, suggesting mBDNF might be involved in regulating metabolism to move through the fed-fast cycle [ 60 , 81 ]. Giacco et al further demonstrated that fasting-induced Bdnf expression is associated with elevated phosphorylation of cAMP-responsive element-binding protein (CREB), TrkB, and AMPK in the skeletal muscle [ 81 ]. Despite the elevated Bdnf expression in Skm, the activity of Akt, a major downstream effector of BDNF-TrkB signaling in neurons [ 82 ], is downregulated during fasting [ 81 ].…”

“…Giacco et al further demonstrated that fasting-induced Bdnf expression is associated with elevated phosphorylation of cAMP-responsive element-binding protein (CREB), TrkB, and AMPK in the skeletal muscle [ 81 ]. Despite the elevated Bdnf expression in Skm, the activity of Akt, a major downstream effector of BDNF-TrkB signaling in neurons [ 82 ], is downregulated during fasting [ 81 ]. Possibly, BDNF might provoke tissue-specific cascades or other fasting-induced responses overwhelm the stimulatory effect of BDNF in muscle during fasting, which requires further exploration.…”

“…It is also interesting to find that AMPK-PGC-1α signaling and mitochondrial content were only reduced in the MBKO mice during fasting but not in the fed status, which reinforces the physiological role of BDNF as a stress-induced myokine to cope with the energy demand [ 60 ]. Presumably, the drop of extracellular glucose and the increase of βHB content in muscle [ 81 ] during fasting promote the BDNF production in muscle fibers, which activates AMPK-PGC-1α pathways to facilitate mitochondrial biogenesis and the glycolysis-to-FAO shift.…”