Spermidine Coupled With Exercise Rescues Skeletal Muscle Atrophy From D-gal-induced Aging Rats Through Enhanced Autophagy and Reduced Apoptosis via AMPK-FOXO3a Signal Pathway

Oncotarget. 2017 Mar 14;8(11):17475-17490. doi: 10.18632/oncotarget.15728.


The quality control of skeletal muscle is a continuous requirement throughout the lifetime, although its functions and quality present as a declining trend during aging process. Dysfunctional or deficient autophagy and excessive apoptosis may contribute to the atrophy of senescent skeletal muscle. Spermidine, as a natural polyamine, can be involved in important cellular functions for lifespan extension and stress resistance in several model organisms through activating autophagy. Similarly, cellular autophagic responses to exercise have also been extensively investigated. In the present study, in order to confirm the mitigation or amelioration of skeletal muscle atrophy in aging rats through spermidine coupled with exercise intervention and explore corresponding mechanisms, the rat model with aging-related atrophy of skeletal muscle was established by intraperitoneal injection of D-galactose (D-gal) (200 mg/kg∙d), and model rats were subjected to the intervention with spermidine (5 mg/kg∙d)) or swimming (60 min/d, 5 d/wk) or combination for 42 days. Spermidine coupled with exercise could attenuate D-gal-induced aging-related atrophy of skeletal muscle through induced autophagy and reduced apoptosis with characteristics of more autophagosomes, activated mitophagy, enhanced mitochondrial quality, alleviated cell shrinkage, and less swollen mitochondria under transmission scanning microscopic observation. Meanwhile, spermidine coupled with exercise could induce autophagy through activating AMPK-FOXO3a signal pathway with characterization of increased Beclin1 and LC3-II/LC3-I ratio, up-regulated anti-apoptotic Bcl-2, down-regulated pro-apoptotic Bax and caspase-3, as well as activated AMPK and FOXO3a. Therefore, spermidine combined with exercise can execute the prevention or treatment of D-gal-induced aging-related skeletal muscle atrophy through enhanced autophagy and reduced apoptosis mediated by AMPK-FOXO3a signal pathway.

Keywords: AMPK-FOXO3a signal pathway; D-galactose; Gerotarget; autophagy; exercise; spermindine.

MeSH terms

  • AMP-Activated Protein Kinases / metabolism
  • Aging / pathology*
  • Animals
  • Apoptosis / drug effects
  • Apoptosis / physiology
  • Autophagy / drug effects
  • Autophagy / physiology
  • Blotting, Western
  • Disease Models, Animal
  • Fluorescent Antibody Technique
  • Forkhead Box Protein O3 / metabolism
  • Galactose / toxicity
  • Immunohistochemistry
  • In Situ Nick-End Labeling
  • Male
  • Microscopy, Electron, Transmission
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / pathology*
  • Muscular Atrophy / pathology
  • Physical Conditioning, Animal*
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Spermidine / pharmacology*


  • Forkhead Box Protein O3
  • FoxO3 protein, mouse
  • AMP-Activated Protein Kinases
  • Spermidine
  • Galactose