Adipose tissue-derived progenitors are essential protagonists of Skeletal Muscle Regeneration – ARMURE

ARMURE application is interested in skeletal muscle biology with specific emphasis on the regenerative process. As a major actor of the locomotion apparatus, skeletal muscles proper regeneration and homeostasis ensures individual mobility and autonomy. For decades, muscle loss of function associated with regeneration defects has been observed in many degenerative conditions whether age-related, or of traumatic, metabolic or of genetic origin. It is therefore easy to understand that defects in muscle regeneration, leading to loss of muscle function, can be massively disabling and have serious clinical and societal consequences.
These muscle degenerative conditions are most often characterized by ectopic fat deposition, in the form of proper adipocytes between muscle fibers, that is largely associated with loss of mechanical and metabolic functions of the skeletal muscle. However, in a totally unexpected way, a transient accumulation of ectopic adipocytes is also described in “normal” skeletal muscles during the regenerative process occurring after injury whose origin and functional role has never been documented, suggesting their positive involvement. In light of previous laboratory data demonstrating that subcutaneous adipose tissue is able to release adipocyte precursors, the so-called adipose stem/stromal cells (ASCs), which could infiltrate the skeletal muscle upon specific metabolic and injury-driven conditions we hypothesize in ARMURE that infiltrated ASC can participate to the transient deposition of intramuscular adipocytes after muscle damage and positively impact the regenerative process.
To test this hypothesis, we’ve imagined an ambitious but realistic project based on a combination of in vitro and ex vivo experiments lying on both mastered and cutting edge technologies as well as original animal models. Our strategy is built up on 3 major objectives. First we aim to characterize the dynamics of ASC-derived adipocytes formation following injury because knowing the precise kinetics of these adipocytes formation and disappearance will offer clues about their function and highlight intervention windows for further functional approaches. In our second objective we propose to study the phenotype of ASC-derived adipocytes among others and profile the lipids they contain because we undoubtedly believe that such metabolites can influence the regenerative process. At last, to definitively demonstrate the beneficial implication of ASC-derived adipocytes in the muscle regenerative process we will study in our third and last objective the influence of ASC-derived adipocytes on the muscle stem cell function in vitro as a prelude start to functional in vivo approaches and then the consequences of their depletion in different animal models. With these integrated in vivo approaches we expect to show that the transient presence of ASC-derived adipocytes is essential to the regenerative muscle function.
To the best of our knowledge, ARMURE offer the first opportunity to reconsider intramuscular adipocytes as a crucial partner for muscle regeneration. Understanding the benefit of these adipocytes for muscle regeneration will offer a unique opportunity to understand why in so many other muscular degenerative conditions they might be deleterious. Knowing how an intramuscular adipocyte should be to be beneficial or supportive for the skeletal muscle will thus have a major impact on potentially all the muscular degenerative conditions mentioned earlier. Beyond the clinical and societal consequences, we can easily imagine the economic impact of restoring the muscle function or at least participating to its rejuvenation. Mobility-enhancing interventions that could stem in the long term from this project could promote successful aging and delay some myopathy conditions.