Autophagy displays divergent roles during intermittent amino acid starvation and toxic stress-induced senescence in cultured skeletal muscle cells

J Cell Physiol. 2021 Apr;236(4):3099-3113. doi: 10.1002/jcp.30079. Epub 2020 Oct 6.

Abstract

Due to the ever-expanding functions attributed to autophagy, there is widespread interest in understanding its contribution to human physiology; however, its specific cellular role as a stress-response mechanism is still poorly defined. To investigate autophagy's role in this regard, we repeatedly subjected cultured mouse myoblasts to two stresses with diverse impacts on autophagic flux: amino acid and serum withdrawal (Hank's balanced salt solution [HBSS]), which robustly induces autophagy, or low-level toxic stress (staurosporine, STS). We found that intermittent STS (int-STS) administration caused cell cycle arrest, development of enlarged and misshapen cells/nuclei, increased senescence-associated heterochromatic foci and senescence-associated β-galactosidase activity, and prevented myogenic differentiation. These features were not observed in cells intermittently incubated in HBSS (int-HB). While int-STS cells displayed less DNA damage (phosphorylated H2A histone family, member X content) and caspase activity when administered cisplatin, int-HB cells were protected from STS-induced cell death. Interestingly, STS-induced senescence was attenuated in autophagy related 7-deficient cells. Therefore, while repeated nutrient withdrawal did not cause senescence, autophagy was required for senescence caused by toxic stress. These results illustrate the context-dependent effects of different stressors, potentially highlighting autophagy as a distinguishing factor.

Keywords: autophagy; caspase; cell death; remodeling; senescence.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / deficiency*
  • Animals
  • Autophagy* / drug effects
  • Cell Cycle Checkpoints / drug effects
  • Cell Death / drug effects
  • Cell Nucleus Shape / drug effects
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Cellular Senescence* / drug effects
  • Mice
  • Muscle Cells / drug effects
  • Muscle Cells / pathology*
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / pathology*
  • Signal Transduction / drug effects
  • Staurosporine / pharmacology
  • Stress, Physiological* / drug effects

Substances

  • Amino Acids
  • Staurosporine