Muscle fiber specific apoptosis and TNF-alpha signaling in sarcopenia are attenuated by life-long calorie restriction

FASEB J. 2005 Apr;19(6):668-70. doi: 10.1096/fj.04-2870fje. Epub 2005 Jan 21.


Increased tumor necrosis factor-alpha (TNF-alpha) levels have been found with age and are connected to muscle atrophy and cell loss, yet the signaling events that occur in vivo are unknown. Calorie restriction (CR), a robust intervention shown to repeatedly evade the physiological declines associated with aging, has been reported to reduce TNF-alpha and may assist in understanding the mechanisms of muscle sarcopenia. The effects of age and CR on muscle mass, myocyte area, fiber number, myocyte TNF-alpha expression, plasma TNF-alpha levels, and specific elements linked with the TNF-alpha signaling cascade (TNF-R1, IKKgamma, IkappaBalpha, p65, NF-kappaB binding activity, FADD, caspase-8, and DNA fragmentation) were investigated in soleus (predominately Type I fiber), and superficial vastus lateralis (SVL, predominately Type II fiber), of 6-month-old ad libitum fed (6AL), 26-month-old ad libitum fed (26AL), and 26-month-old calorie-restricted (26CR) male Fischer 344 rats (CR = 40% restriction compared with ad libitum). Plasma TNF-alpha was increased with age, and the age-associated rise was attenuated with life-long CR. In soleus muscle, we reported a greater capacity to cultivate inflammatory signaling through the transcription factor NF-kappaB compared with that detected in SVL with age. In contrast, in the SVL TNF-alpha stimulated apoptotic signaling with age to a much higher extent than was observed in the soleus. Moreover, a reduction in muscle mass, cross-sectional area, and fiber number in the SVL coincided with this age-linked elevation in apoptosis. In agreement with CR's ability, TNF-alpha stimulation of both inflammatory and apoptotic pathways were abrogated. Our results suggest that TNF-alpha signals transmitted to specific fiber types determine the decision of selecting life or death signaling pathways and are linked to the extent of fiber loss experienced in the aging muscle. Such a specific potential may constitute a major proponent in the pathogenesis of sarcopenia.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aging
  • Animals
  • Apoptosis*
  • Caloric Restriction*
  • Cell Fractionation
  • Cell Nucleus / metabolism
  • Cell Nucleus / ultrastructure
  • Cytosol / chemistry
  • Cytosol / ultrastructure
  • DNA Fragmentation
  • Male
  • Muscle Cells / chemistry
  • Muscle Fibers, Fast-Twitch / pathology
  • Muscle Fibers, Skeletal / pathology*
  • Muscle Fibers, Slow-Twitch / pathology
  • Muscle, Skeletal / pathology
  • Muscular Atrophy / pathology
  • Muscular Atrophy / physiopathology
  • Muscular Atrophy / prevention & control*
  • NF-kappa B / analysis
  • NF-kappa B / metabolism
  • Organ Size
  • Rats
  • Rats, Inbred F344
  • Signal Transduction / physiology*
  • Tumor Necrosis Factor-alpha / analysis
  • Tumor Necrosis Factor-alpha / physiology*


  • NF-kappa B
  • Tumor Necrosis Factor-alpha