Contractile work directly modulates mitochondrial protein levels in human engineered heart tissues

Area of Science:

• Biomedical Engineering
• Cardiovascular Research
• Cellular Physiology

Background:

• Engineered heart tissues (EHTs) are valuable in vitro models for cardiac physiology.
• Existing culture methods struggle to replicate the full cardiac cycle's mechanical demands.
• A novel bioreactor is needed to simulate in vivo cardiac work loops for EHTs.

Purpose of the Study:

• To develop and utilize a novel bioreactor for culturing EHTs under dynamic, in vivo-like mechanical loading conditions.
• To investigate the impact of cyclic loading and work loops on EHT contractility and mitochondrial adaptation.
• To determine the relationship between mechanical work output and mitochondrial biogenesis in EHTs.

Main Methods:

• Development of a bioreactor enabling precise control of cyclic loading and work loops in EHTs.
• Culture of EHTs under various loading regimes, including isometric and dynamic work loops.
• Assessment of EHT concentric and isometric contractions, contractile work capacity.
• Quantification of mitochondrial protein levels and mitochondrial biogenesis markers.

Main Results:

• EHTs cultured under cyclic work loops exhibited enhanced concentric contractions and increased contractile work capacity.
• Increased work production correlated with higher mitochondrial protein levels and enhanced mitochondrial biogenesis.
• Mitochondrial adaptation was dependent on mechanical work output, not solely afterload.
• The effects of cyclic shortening on mitochondrial adaptation were abolished by myosin ATPase inhibition.

Conclusions:

• The novel bioreactor successfully recapitulates cardiac work loops, enabling advanced EHT culture.
• Mechanical work performed by EHTs in culture is a potent regulator of mitochondrial mass and biogenesis.
• This study provides a new in vitro platform for investigating cardiac adaptation to mechanical stimuli.