Exercise and fasting via beta hydroxybutyrate ( signaling, direct priming of oxidative phosphorylation and histone acetylase inhibition to increase BDNF transcription) increase nuclear transcription factors of BDNF et al and are promoted by PPAR gamma agonist such as Ursolic acid via peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α.
BHB beta hydroxybutyrate is the transcriptional link allowing PGC1α and NCOR1 to co-promote or co-repress oxidative phosphorylation .
More fasting, exercise and high fat low carb diet promotes mitochondrial metabolism via BHB nuclear transcription of BDNF et al and increased PgC1a or decreased NCOR1 an amplifying or silencing partner effecting the mitochondria.
Ursolic acid, amplifies fasting and exercise effects of BDNF leading to increased fatty acid oxidation and energy production by mitochondria. The effect in muscles is 30% more strength in 8 weeks and I suspect increased nerve and brain metabolism and function. One important function of brain energy is to protect the brain! What is the most potent nuclear transcription growth factor to prevent brain disconnection syndrome? BDNF brain derived neurotrophic factor. BDNF also inhibit heart and muscle disconnection syndrome that leads to heart failure and age related sarcopenia.
Introduction
Energy is vital to all living organisms. In humans and other mammals, the vast majority of energy is produced by oxidative metabolism in mitochondria [1]. As a cellular organelle, mitochondria are under tight control of the nucleus. Although the majority of mitochondrial proteins are encoded by nuclear DNA (nDNA) and their expression regulated by the nucleus, mitochondria retain their own genome, mitochondrial DNA (mtDNA), encoding 13 polypeptides of the electron transport chain (ETC) in mammals. However, all proteins required for mtDNA replication, transcription, and translation, as well as factors regulating such activities, are encoded by the nucleus [2].
The cellular demand for energy varies in different cells under different physiological conditions. Accordingly, the quantity and activity of mitochondria are differentially controlled by a transcriptional regulatory network in both the basal and induced states. A number of components of this network have been identified, including members of the nuclear receptor superfamily, the peroxisome proliferator-activated receptors (PPARs) and the estrogen-related receptors (ERRs) [3, 4 and 5].
The Yin-Yang co-regulators
A well-known inducer of mitochondrial oxidative metabolism is the peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α) [6], a nuclear cofactor which is abundantly expressed in high energy demand tissues such as heart, skeletal muscle, and brown adipose tissue (BAT) [7]. Induction by cold-exposure, fasting, and exercise allows PGC1α to regulate mitochondrial oxidative metabolism by activating genes involved in the tricarboxylic acid cycle (TCA cycle), beta-oxidation, oxidative phosphorylation (OXPHOS), as well as mitochondrial biogenesis [6 and 8] (Figure 1).
Figure 1. PPARs and ERRs are major executors of PGC1α-induced regulation of oxidative metabolism. Physiological stress such as exercise induces both the expression and activity of PGC1α, which stimulates energy production by activating downstream genes involved in fatty acid and glucose metabolism, TCA cycle, β-oxidation, OXPHOS, and mitochondrial biogenesis. The transcriptional activity of PGC1α relies on its interactions with transcriptional factors such as PPARs (for controlling fatty acid metabolism) and ERRs (for regulating mitochondrial OXPHOS).
The effect of PGC1α on mitochondrial regulation is antagonized by transcriptional corepressors such as the nuclear receptor corepressor 1 (NCOR1) [9 and 10]. In contrast to PGC1α, the expression of NCOR1 is suppressed in conditions where PGC1α is induced such as during fasting, high-fat-diet challenge, and exercise [9 and 11]. Moreover, the knockout of NCOR1 phenotypically mimics PGC1α overexpression in regulating mitochondrial oxidative metabolism [9]. Therefore, coactivators and corepressors collectively regulate mitochondrial metabolism in a Yin-Yang fashion.
However, both PGC1α and NCOR1 lack DNA binding activity and rather act via their interaction with transcription factors that direct the regulatory program. Therefore the transcriptional factors that partner with PGC1α and NCOR1 mediate the molecular signaling cascades and execute their inducible effects on mitochondrial regulation.
Joseph Thomas (Tony) Liverman, Jr.
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