PMID- 36708027
OWN - NLM
STAT- MEDLINE
DCOM- 20230407
LR  - 20230407
IS  - 2190-6009 (Electronic)
IS  - 2190-5991 (Print)
IS  - 2190-5991 (Linking)
VI  - 14
IP  - 2
DP  - 2023 Apr
TI  - Mesenchymal stromal cells ameliorate diabetes-induced muscle atrophy through 
      exosomes by enhancing AMPK/ULK1-mediated autophagy.
PG  - 915-929
LID - 10.1002/jcsm.13177 [doi]
AB  - BACKGROUND: Diabetes and obesity are associated with muscle atrophy that reduces 
      life quality and lacks effective treatment. Mesenchymal stromal cell (MSC)-based 
      therapy can ameliorate high fat-diet (HFD) and immobilization (IM)-induced muscle 
      atrophy in mice. However, the effect of MSCs on muscle atrophy in type 2 diabetes 
      mellitus (T2DM) and the potential mechanism is unclear. Here, we evaluated the 
      efficacy and explored molecular mechanisms of human umbilical cord MSCs (hucMSCs) 
      and hucMSC-derived exosomes (MSC-EXO) on diabetes- and obesity-induced muscle 
      atrophy. METHODS: Diabetic db/db mice, mice fed with high-fat diet (HFD), mice 
      with hindlimb immobilization (IM), and C2C12 myotubes were used to explore the 
      effect of hucMSCs or MSC-EXO in alleviating muscle atrophy. Grip strength test 
      and treadmill running were used to measure skeletal muscle strength and 
      performance. Body composition, muscle weight, and muscle fibre cross-sectional 
      area (CSA) was used to evaluate muscle mass. RNA-seq analysis of tibialis 
      anterior (TA) muscle and Western blot analysis of muscle atrophy signalling, 
      including MuRF1 and Atrogin 1, were performed to investigate the underlying 
      mechanisms. RESULTS: hucMSCs increased grip strength (P = 0.0256 in db/db mice, 
      P = 0.012 in HFD mice, P = 0.0097 in IM mice), running endurance (P = 0.0154 in 
      HFD mice, P = 0.0006 in IM mice), and muscle mass (P = 0.0004 in db/db mice, 
      P = 0.0076 in HFD mice, P = 0.0144 in IM mice) in all models tested, with 
      elevated CSA of muscle fibres (P < 0.0001 in db/db mice and HFD mice, P = 0.0088 
      in IM mice) and reduced Atrogin1 (P = 0.0459 in db/db mice, P = 0.0088 in HFD 
      mice, P = 0.0016 in IM mice) and MuRF1 expression (P = 0.0004 in db/db mice, 
      P = 0.0077 in HFD mice, P = 0.0451 in IM mice). MSC-EXO replicated all these 
      hucMSC-mediated changes (P = 0.0103 for grip strength, P = 0.013 for muscle mass, 
      P < 0.0001 for CSA of muscle fibres, P = 0.0171 for Atrogin1 expression, and 
      P = 0.006 for MuRF1 expression). RNA-seq revealed that hucMSCs activated the 
      AMPK/ULK1 signalling and enhanced autophagy. Knockdown of AMPK or inhibition of 
      autophagy with 3-methyladenine (3-MA) diminished the beneficial anti-atrophy 
      effects of hucMSCs or MSC-EXO. CONCLUSIONS: Our results suggest that human 
      umbilical cord mesenchymal stromal cells mitigate diabetes- and obesity-induced 
      muscle atrophy via enhancing AMPK/ULK1-mediated autophagy through exosomes, with 
      implications of applying hucMSCs or hucMSC-derived exosomes to treat muscle 
      atrophy.
CI  - (c) 2023 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John 
      Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting 
      Disorders.
FAU - Song, Jia
AU  - Song J
AD  - Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 
      Shandong, China.
FAU - Liu, Jidong
AU  - Liu J
AD  - Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 
      Shandong, China.
FAU - Cui, Chen
AU  - Cui C
AD  - Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 
      Shandong, China.
FAU - Hu, Huiqing
AU  - Hu H
AD  - Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 
      Shandong, China.
FAU - Zang, Nan
AU  - Zang N
AD  - Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 
      Shandong, China.
FAU - Yang, Mengmeng
AU  - Yang M
AD  - Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 
      Shandong, China.
FAU - Yang, Jingwen
AU  - Yang J
AD  - Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 
      Shandong, China.
FAU - Zou, Ying
AU  - Zou Y
AD  - Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 
      Shandong, China.
FAU - Li, Jinquan
AU  - Li J
AD  - Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 
      Shandong, China.
FAU - Wang, Lingshu
AU  - Wang L
AD  - Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 
      Shandong, China.
FAU - He, Qin
AU  - He Q
AD  - Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 
      Shandong, China.
FAU - Guo, Xinghong
AU  - Guo X
AD  - Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 
      Shandong, China.
FAU - Zhao, Ruxing
AU  - Zhao R
AD  - Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 
      Shandong, China.
FAU - Yan, Fei
AU  - Yan F
AD  - Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 
      Shandong, China.
FAU - Liu, Fuqiang
AU  - Liu F
AD  - Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 
      Shandong, China.
FAU - Hou, Xinguo
AU  - Hou X
AD  - Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 
      Shandong, China.
AD  - Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, 
      Shandong, China.
AD  - Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & 
      Health, Jinan, Shandong, China.
AD  - Jinan Clinical Research Center for Endocrine and Metabolic Disease, Jinan, 
      Shandong, China.
FAU - Sun, Zheng
AU  - Sun Z
AD  - Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 
      Shandong, China.
FAU - Chen, Li
AU  - Chen L
AD  - Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 
      Shandong, China.
AD  - Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, 
      Shandong, China.
AD  - Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & 
      Health, Jinan, Shandong, China.
AD  - Jinan Clinical Research Center for Endocrine and Metabolic Disease, Jinan, 
      Shandong, China.
LA  - eng
GR  - 82070800/National Natural Science Foundation of China/
GR  - ts201712089/Taishan Scholar Foundation of Shandong Province/
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230127
PL  - Germany
TA  - J Cachexia Sarcopenia Muscle
JT  - Journal of cachexia, sarcopenia and muscle
JID - 101552883
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
RN  - EC 2.7.11.1 (Autophagy-Related Protein-1 Homolog)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - EC 2.7.11.1 (ULK1 protein, human)
SB  - IM
MH  - Animals
MH  - Humans
MH  - Mice
MH  - AMP-Activated Protein Kinases/metabolism
MH  - Autophagy
MH  - Autophagy-Related Protein-1 Homolog/metabolism
MH  - *Diabetes Mellitus, Type 2/complications/therapy
MH  - *Exosomes/metabolism
MH  - Intracellular Signaling Peptides and Proteins/metabolism
MH  - *Mesenchymal Stem Cells/metabolism
MH  - *Muscular Atrophy/etiology/therapy/metabolism
MH  - Obesity
PMC - PMC10067482
OTO - NOTNLM
OT  - AMPK/ULK1
OT  - Autophagy
OT  - Exosome
OT  - Muscle atrophy
OT  - hucMSCs
COIS- All authors declare that they have no competing interests.
EDAT- 2023/01/29 06:00
MHDA- 2023/04/04 06:42
PMCR- 2023/01/27
CRDT- 2023/01/28 01:43
PHST- 2022/11/21 00:00 [revised]
PHST- 2022/06/21 00:00 [received]
PHST- 2023/01/02 00:00 [accepted]
PHST- 2023/04/04 06:42 [medline]
PHST- 2023/01/29 06:00 [pubmed]
PHST- 2023/01/28 01:43 [entrez]
PHST- 2023/01/27 00:00 [pmc-release]
AID - JCSM13177 [pii]
AID - 10.1002/jcsm.13177 [doi]
PST - ppublish
SO  - J Cachexia Sarcopenia Muscle. 2023 Apr;14(2):915-929. doi: 10.1002/jcsm.13177. 
      Epub 2023 Jan 27.