Type 5 adenylyl cyclase disruption leads to enhanced exercise performance

Area of Science:

• Physiology
• Molecular Biology
• Gerontology

Background:

• Enhanced exercise performance is typically linked to increased sympathetic signaling via beta-adrenergic receptors (β-AR) and adenylyl cyclase (AC) activity.
• This study challenges that paradigm by investigating the role of decreased AC activity in exercise performance.

Purpose of the Study:

• To investigate the effects of disrupting adenylyl cyclase 5 (AC5) on exercise performance and longevity.
• To elucidate the underlying molecular mechanisms, including mitochondrial biogenesis and oxidative stress pathways.

Main Methods:

• Utilized AC5 knockout (KO) mice, including cardiac- and skeletal muscle-specific KO models.
• Examined molecular markers such as SIRT1, FoxO3a, MEK, and MnSOD.
• Employed pharmacological inhibitors and genetic crosses to confirm mechanistic pathways.
• Investigated the conserved pathway in Caenorhabditis elegans using RNA interference (RNAi).

Main Results:

• AC5 disruption significantly increased exercise performance in mice, including in aged individuals.
• The benefits were localized to skeletal muscle, not the heart.
• Key pathways upregulated included mitochondrial biogenesis, SIRT1, FoxO3a, MEK, and the antioxidant MnSOD.
• Inhibition of SIRT1 or MEK, or reduced MnSOD, blocked the exercise performance enhancement.
• Conserved benefits on fitness, mitochondrial function, and lifespan were observed in C. elegans with acy-3 knockdown.

Conclusions:

• Decreased AC5 activity enhances exercise performance and promotes longevity through mechanisms involving skeletal muscle mitochondrial biogenesis and antioxidant defense.
• This pathway represents a novel target for improving both physical capacity and healthy aging.
• The findings highlight a conserved mechanism across species for enhancing fitness and lifespan by modulating AC5 activity.