Sirt6 reprograms myofibers to oxidative type through CREB-dependent Sox6 suppression

Area of Science:

• Molecular Biology
• Exercise Physiology
• Metabolic Diseases

Background:

• Obesity-related metabolic diseases can be combatted by increasing skeletal muscle exercise capacity.
• Shifting skeletal muscle fibers to a slow-twitch oxidative type enhances muscle function.
• Sirtuin 6 (Sirt6), an anti-aging histone deacetylase, plays a role in regulating muscle fiber type.

Purpose of the Study:

• To investigate the role of Sirt6 in regulating skeletal muscle fiber type and exercise capacity.
• To determine if Sirt6 activation can mimic exercise effects.
• To elucidate the molecular mechanisms by which Sirt6 influences muscle fiber composition.

Main Methods:

• Genetic inactivation and transgenic overexpression of Sirt6 in mouse skeletal muscle.
• Assessment of mitochondrial oxidative capacity and exercise performance in mice.
• Analysis of Sirt6's effect on Sox6 and CREB (cAMP response element-binding protein) gene expression.

Main Results:

• Skeletal muscle-specific Sirt6 inactivation reduced, while overexpression increased, mitochondrial oxidative capacity and exercise performance in mice.
• Sirt6 was found to downregulate Sox6 by increasing CREB transcription, promoting a slow-twitch oxidative fiber type.
• Sirt6 activator treatment in mice increased exercise endurance, comparable to exercise-trained controls.

Conclusions:

• Sirt6 is a critical regulator of skeletal muscle fiber type, promoting an oxidative phenotype.
• Sirt6 activation can serve as an 'exercise mimetic' strategy to improve muscle performance.
• Targeting Sirt6 offers a novel therapeutic approach for metabolic diseases and enhancing muscle function.