Abstract
To extend life expectancy and ensure healthy aging, it is crucial to prevent and minimize age‐induced skeletal muscle atrophy, also known as sarcopenia. However, the disease's molecular mechanism remains unclear. The age‐related Wnt/β‐catenin signaling pathway has been recently shown to be activated by the (pro)renin receptor ((P)RR). We report here that (P)RR expression was increased in the atrophied skeletal muscles of aged mice and humans. Therefore, we developed a gain‐of‐function model of age‐related sarcopenia via transgenic expression of (P)RR under control of the CAG promoter. Consistent with our hypothesis, (P)RR‐Tg mice died early and exhibited muscle atrophy with histological features of sarcopenia. Moreover, Wnt/β‐catenin signaling was activated and the regenerative capacity of muscle progenitor cells after cardiotoxin injury was impaired due to cell fusion failure in (P)RR‐Tg mice. In vitro forced expression of (P)RR protein in C2C12 myoblast cells suppressed myotube formation by activating Wnt/β‐catenin signaling. Administration of Dickkopf‐related protein 1, an inhibitor of Wnt/β‐catenin signaling, and anti‐(P)RR neutralizing antibody, which inhibits binding of (P)RR to the Wnt receptor, significantly improved sarcopenia in (P)RR‐Tg mice. Furthermore, the use of anti‐(P)RR neutralizing antibodies significantly improved the regenerative ability of skeletal muscle in aged mice. Finally, we show that Yes‐associated protein (YAP) signaling, which is coordinately regulated by Wnt/β‐catenin, contributed to the development of (P)RR‐induced sarcopenia. The present study demonstrates the use of (P)RR‐Tg mice as a novel sarcopenia model, and shows that (P)RR‐Wnt‐YAP signaling plays a pivotal role in the pathogenesis of this disease.
Highlights
Developed countries are characterized by a rapidly aging population
We examined whether ubiquitin–proteasome pathway (UPP) and mTOR pathways were involved in muscle atrophy in (P)RR‐Tg mice
These results suggested that autophagy dysfunction induced by the acti‐ vation of (P)RR‐Wnt‐Yes‐associated protein (YAP) signaling caused initiation of sarcopenia in (P)RR‐Tg mice and led to myocytes’ death and subsequent mus‐ cle regeneration
Summary
Developed countries are characterized by a rapidly aging population. Age‐related muscle atrophy, known as sarcopenia, is associated with adverse health outcomes including disability, hospitalization, poor quality of life, and mortality. KEYWORDS (pro)renin receptor, aging, canonical Wnt pathway, sarcopenia, skeletal muscle atrophy, YAP signaling We demonstrated an increase in (P)RR protein expression following activation of the Wnt pathway in atrophied skeletal muscles of senile mice and humans.
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