Activation of mitochondrial biogenesis
PGC1α-dependent mitochondriogenic pathway and its pharmacological modulation
Stimulation of mitochondrial oxidative-phosphorylation-related transcriptional pathways can be obtained by activating Pgc1α related transcriptional pathways. Pgc1α can be activated either by phosphorylation by AMP-kinase (AMPK) or deacetylation by Sirtuin1 (Sirt1). Sirt1 is a NAD+ dependent nuclear deacetylase, and NAD+ precursors, such as Nicotinamide or Nicotinamide Riboside, are effective Sirt1 activators.
Pharmacological inhibition of Parp1, the principal NAD+ consumer in cells, or administration of nicotinamide riboside, NR, a natural NAD+ precursor, activates Pgc1α through a Sirt1-dependent mechanism, boosts the transcription of mitochondrial genes, and increases the activity of the respiratory chain, leading to a significant improvement, up to norm, of the endurance motor performance of a mouse model of mitochondrial myopathy associated with defective cytochrome-c oxidase.
Effects of NAD+ modulation on the skeletal muscle of a mouse model of mitochondrial myopathy
Both Nicotinamide Riboside and Parp inhibitors increase NAD+ concentration in skeletal muscle, thus boosting Sirt1 activity. Sirt1 activation results in the deacetylation of Pgc1α and activation of mitochondrial biogenesis, which partially corrects the COX defect.