Muscle immobilization activates mitophagy and disrupts mitochondrial dynamics in mice

Choung-Hun Kang, D. Yeo, Li Li Ji

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

Aim: Skeletal muscle atrophy following prolonged immobilization (IM) is a catabolic state characterized by increased proteolysis and functional deterioration. Previous research indicates that discord of mitochondrial homoeostasis plays a critical role in muscle atrophy. We hypothesized that muscle IM would activate the ubiquitin-proteolysis, autophagy–lysosome (mitophagy) pathway, mitochondrial dynamics remodelling and apoptosis partially controlled by the FoxO signalling pathway. Methods: Female FVB/N mice were randomly divided into five groups (n = 8 each): control (CON), IM with banding of one of the hindlimbs for 1, 2 and 3 weeks (1w-, 2w- and 3w-IM) and 2w-IM followed by 1 week of remobilization (RM). Results: Mitochondrial density and DNA copies in tibialis anterior (TA) muscle were reduced by approx. 80% (P < 0.05 for 2w-IM; P < 0.01 for 3w-IM), along with activation of FoxO3a, atrogin-1 and MuRF1 following 2w- and 3w-IM (P < 0.01). Protein markers of autophagy/mitophagy, such as beclin 1 (approx. 2.7-fold; P < 0.01), LC3, ubiquitin-binding adaptor (approx. 1.47-fold; P < 0.01), Rheb (approx. 1.9-fold; P < 0.05) and parkin (approx. 70%; P < 0.05), were all increased by IM and remained activated after RM, whereas BNIP3 and PINK1 levels were decreased by IM (P < 0.05), but elevated upon RM (P < 0.01). IM decreased Mfn2 expression (approx. 50%; P < 0.01) and increased Fis-1 expression (approx. 2.4-fold; P < 0.05). Muscle apoptosis indicator Bax/Bcl2 ratio was elevated at 2w- to 3w-IM (approx. 3.7-fold; P < 0.01), whereas caspase-3 activity was five- to sixfold higher (P < 0.01) and remained threefold higher above CON (P < 0.05). Conclusion: Our data indicate that IM-induced mitochondrial deterioration is associated with altered protein expressions in the autophagic/mitophagic pathway, more fragmented mitochondrial network and activation of apoptosis partly under the influence of FoxO3 activation.

Original languageEnglish (US)
Pages (from-to)188-197
Number of pages10
JournalActa Physiologica
Volume218
Issue number3
DOIs
StatePublished - Nov 1 2016

Keywords

  • FoxO3
  • atrophy
  • immobilization
  • mitochondrial dynamics
  • mitophagy
  • skeletal muscle

Fingerprint Dive into the research topics of 'Muscle immobilization activates mitophagy and disrupts mitochondrial dynamics in mice'. Together they form a unique fingerprint.

Cite this