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               Extracellular vesicles derived from Cicer arietinum improve dexamethasone-

               induced sarcopenia through regulation of AMPK-mTOR signal


                                                                                                        1,2
                                               1,2
                                                                     1,2
                                                                                     1,2
               HyunSoo Yang,   #,1,2   Mina  Boo,   Hyunyoung  Choi,   Suhyeon An,   Jae  Heon  Sim,
               Dong-Hyun Youn,  Hye-Lin Kim,     Jinbong Park*
                                                 2
                                                                    ,2
                                  2

               1  Department of Science in Korean Medicine, Graduate School, Kyung Hee University, Seoul,
                 Republic of Korea
               2  Department of Pharmacology, College of Korean Medicine, Kyung Hee University, Seoul,
                 Republic of Korea
               * E-mail: thejinbong@khu.ac.kr

               Abstract
                  Sarcopenia, defined as the progressive loss of skeletal muscle mass and function, represents
               a growing global health challenge driven by aging, malnutrition, physical inactivity, hormonal
               imbalance,  and  cachexia-associated  diseases.  Despite  its  clinical  importance,  there  are  no
               pharmacological  treatments  currently  available.  Plant-derived  exosomes  have  emerged  as
               promising therapeutic nanomaterials owing to their biocompatibility, low immunogenicity, and
               oral bioavailability. In this study, we evaluated the anti-sarcopenic potential of Cicer arietinum-
               derived extrracellular vesicles (CAEVs), a previously unexplored source enriched in protein
               and  antioxidants.  Using  a  dexamethasone-induced  sarcopenia  model,  we  investigated  their
               therapeutic  effects  and  underlying  mechanisms,  focusing  on AMP-activated  protein  kinase
               (AMPK)  and  mammalian  target  of  rapamycin  (mTOR)  signaling  pathways.  CAEVs
               significantly  attenuated  dexamethasone-induced  atrophy  of  C2C12  cells,  evidenced  by
               preserved myotube morphology. In vivo, CAEV treatment restored muscle mass and improved
               muscle  function  compared  to  dexamethasone-injected  control  mice.  Mechanistically,  their
               protective  effects  were  mediated  by  AMPK  activation  and  subsequent  mTOR  signaling.
               Inhibition of AMPK with compound c pre-treatment revoked the effect of CAEVs on muscle
               preservation.  Additionally,  CAEVs  enhanced  ppar  gamma-coactivator  1  alpha  (PGC-1α)
               expression and mitochondrial biogenesis. To our knowledge, this is the first demonstration that
               CAEVs can prevent muscle atrophy by modulating key metabolic pathways, highlighting their
               potential as a natural and clinically translatable therapeutic strategy for sarcopenia.

               Keywords:  Cicer  arietinum  (Chickpea);  Plant-derived  extracellular  vesicles;  Sarcopenia;
                           Dexamethasone; C2C12 cells; Muscle atrophy
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