| The stark reduction in muscle mass and function noted with age, termed sarcopenia, is a normal yet debilitative feature of aging. Stemming from the lack of clarity surrounding the role of TNF-alpha in age-associated muscle loss, we investigated the involvement of this cytokine in promoting reductions in muscle mass, and the cellular signaling pathways through which these effects were executed. We studied the inflammatory and apoptotic pathways emanating from TNF-alpha stimulation in the muscle cells, and also compared the responses to TNF-alpha in two different muscles, the soleus and the superficial vastus lateralis. These muscles were selected as they contained different types of muscle fibers known to exhibit the effects of aging (i.e., muscle loss) to differing degrees. We found that aging was paralleled with increased TNF-alpha, and that the inflammatory and apoptotic signaling capability of TNF-alpha was dependent on the muscle being examined. In the soleus with age, we report a greater capacity to cultivate inflammatory signaling through the transcription factor, NF-kappaB, compared to that detected in the superficial vastus lateralis. Alternatively, in the superficial vastus lateralis, TNF-alpha stimulated apoptotic signaling with age to a much higher extent than was observed in the soleus. Moreover, a reduction in muscle cell area in the superficial vastus lateralis coincided with this age-linked elevation in apoptosis.;Application of the life-extending intervention, calorie restriction, was also relied upon to provide further elucidation of the contribution of TNF-alpha to skeletal muscle loss with age. Calorie restriction is the only robust intervention shown to repeatedly evade the physiological declines associated with aging, and in agreement with this ability, TNF-alpha stimulation of both inflammatory and apoptotic pathways were abrogated when calorie restriction was applied. Our results suggest that specific fiber types may play a regulatory role in determining the nature of the TNF-alpha signal transmitted at the cellular level, with the decision of selecting life or death signals intimately tied to the extent of fiber loss experienced in the muscle; such a potential may constitute a major proponent in the pathogenesis of sarcopenia. |
