Affiliation:
1. Department of Physical Medicine and Rehabilitation University of Pittsburgh Pittsburgh PA 15213 USA
2. Discovery Center for Musculoskeletal Recovery Schoen Adams Research Institute at Spaulding Charlestown MA 02129 USA
3. Department of Physical Medicine and Rehabilitation Harvard Medical School Boston MA 02115 USA
4. Department of Bioengineering University of Pittsburgh Pittsburgh PA 15213 USA
5. Department of Medicine Division of Geriatric Medicine University of Pittsburgh Pittsburgh PA 15213 USA
6. McGowan Institute for Regenerative Medicine University of Pittsburgh Pittsburgh PA 15213 USA
Abstract
AbstractA mechanistic understanding of cell‐autonomous skeletal muscle changes after injury can lead to novel interventions to improve functional recovery in an aged population. However, major knowledge gaps persist owing to limitations of traditional biological aging models. 2D cell culture represents an artificial environment, while aging mammalian models are contaminated by influences from non‐muscle cells and other organs. Here, a 3D muscle aging system is created to overcome the limitations of these traditional platforms. It is shown that old muscle constructs (OMC) manifest a sarcopenic phenotype, as evidenced by hypotrophic myotubes, reduced contractile function, and decreased regenerative capacity compared to young muscle constructs. OMC also phenocopy the regenerative responses of aged muscle to two interventions, pharmacological and biological. Interrogation of muscle cell‐specific mechanisms that contribute to impaired regeneration over time further reveals that an aging‐induced increase of complement component 4b (C4b) delays muscle progenitor cell amplification and impairs functional recovery. However, administration of complement factor I, a C4b inactivator, improves muscle regeneration in vitro and in vivo, indicating that C4b inhibition may be a novel approach to enhance aged muscle repair. Collectively, the model herein exhibits capabilities to study cell‐autonomous changes in skeletal muscle during aging, regeneration, and intervention.
Funder
National Institute on Aging
Army Research Laboratory
National Institutes of Health
Subject
Mechanical Engineering,Mechanics of Materials,General Materials Science
Cited by
4 articles.
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