Engineering biomimetic skeletal muscle systems that can model age-related muscle functional declines provides promising opportunities for understanding muscle aging and drug testing. In this project, we are developing three-dimensional muscle constructs using skeletal muscle progenitor cells isolated from young or aged mice and we are validating the ability of our constructs to reconstitute the molecular and cellular events of muscle aging. To date, we have observed highly aligned myotubes in both young muscle constructs (YMC) and old muscle constructs (OMC) after maturation. However, OMC contained smaller myotubes with a lower percentage of striated myotubes than the YMC. As a result, OMC exhibited limited force generation and calcium handling capacities compared to the young counterparts. This is consistent with well-established sarcopenic declines in older individuals. Furthermore, our preliminary data reveals that, in response to cardiotoxin injury, OMC exhibited impaired myotube regeneration and force recovery compared to YMC. This impaired regenerative response with aging is consistent with observations in mouse and human models. As a proof-of-concept of drug testing, our next steps are to evaluate the beneficial effects of extracellular vesicles (EVs) from young mouse serum on the recovery of injured muscle constructs, as these EVs have been shown to enhance aged muscle regeneration in vivo in our previous study. Collectively, this project aims to provide a powerful muscle aging platform that can be used to investigate the mechanisms that drive the declined muscle function with aging and evaluate the performance of therapeutic drugs for muscle repair.

Collaborator: Sanjeev Shroff, PhD, Distinguished Professor and Gerald E. Mcginnis Chair in Bioengineering, University of Pittsburgh, USA