Skeletal muscle SIRT1 and the genetics of metabolic health: therapeutic activation by pharmaceuticals and exercise

Figures & data

Figure 1 Model of pathways leading to activation of the silent mating type information regulation 2 homolog 1 (SIRT1)/peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) axis in skeletal muscle: SIRT1 deacetylase activity is directly influenced through posttranslational modification and indirectly through exercise, caloric restriction, and pharmaceutical activation.

Notes: Exercise-induced activation of adenosine monophosphate-activated protein kinase increases nicotinamide adenine dinucleotide, a necessary substrate in the SIRT1 deacetylase reaction, and directly phosphorylates cytosolic PGC-1α prior to nuclear translocation. Caloric restriction activates adenosine monophosphate-activated protein kinase and increases nicotinamide adenine dinucleotide, while pharmaceuticals (resveratrol/SRT1720) activate adenosine monophosphate-activated protein kinase, induce SIRT1 posttranslational modification, and may augment SIRT1 deacetylase activity through direct interaction (dashed line). SIRT1 activates PGC-1α through deacetylation, increasing PGC-1α-mediated autoexpression and transcription of mitochondrial genes.
Abbreviations: Ac, acetyl; ADP, adenosine diphosphate; AMP, adenosine monophosphate; AMPK, adenosine monophosphate-activated protein kinase; ATP, adenosine triphosphate; NAD⁺, nicotinamide adenine dinucleotide; P, phosphate; PGC-1α, peroxisome proliferator-activated receptor γ coactivator-1α; PTM, posttranslational modification; SIRT1, silent mating type information regulation 2 homolog 1.