Agent-based computational model investigates muscle-specific responses to disuse-induced atrophy

Abstract

Martin KS, Blemker SS, Peirce SM. Agent-based computational model investigates muscle-specific responses to disuse-induced atrophy. J Appl Physiol 118: 1299 -1309, 2015. First published February 26, 2015 doi:10.1152/japplphysiol.01150.2014.-Skeletal muscle is highly responsive to use. In particular, muscle atrophy attributable to decreased activity is a common problem among the elderly and injured/ immobile. However, each muscle does not respond the same way. We developed an agent-based model that generates a tissue-level skeletal muscle response to disuse/immobilization. The model incorporates tissue-specific muscle fiber architecture parameters and simulates changes in muscle fiber size as a result of disuse-induced atrophy that are consistent with published experiments. We created simulations of 49 forelimb and hindlimb muscles of the rat by incorporating eight fiber-type and size parameters to explore how these parameters, which vary widely across muscles, influence sensitivity to disuse-induced atrophy. Of the 49 muscles modeled, the soleus exhibited the greatest atrophy after 14 days of simulated immobilization (51% decrease in fiber size), whereas the extensor digitorum communis atrophied the least (32%). Analysis of these simulations revealed that both fibertype distribution and fiber-size distribution influence the sensitivity to disuse atrophy even though no single tissue architecture parameter correlated with atrophy rate. Additionally, software agents representing fibroblasts were incorporated into the model to investigate cellular interactions during atrophy. Sensitivity analyses revealed that fibroblast agents have the potential to affect disuse-induced atrophy, albeit with a lesser effect than fiber type and size. In particular, muscle atrophy elevated slightly with increased initial fibroblast population and increased production of TNF-␣. Overall, the agent-based model provides a novel framework for investigating both tissue adaptations and cellular interactions in skeletal muscle during atrophy. agent-based model; muscle atrophy; fiber type; tissue architecture; fibroblasts SKELETAL MUSCLE ADAPTS to activity levels, where elevated activity leads to increases in muscle size (muscle hypertrophy) and diminished activity levels lead to decreases in muscle size (muscle atrophy) (6, 36).1 Muscle atrophy is estimated to affect 45% of the U.S. elderly population and directly attributed to 1.5% of total direct healthcare costs in 2000 ($18.5 billion) (25). In young people, diminished activity as a consequence of surgery-related immobilization (2, 68), bed rest (33), or long-term mechanical ventilation (34) lead to disabling muscle weakness.Muscle atrophy, triggered by loss of mechanical stimulation, causes changes in the behavior of the various cell types that comprise muscle tissue (52, 53). Muscle fiber protein production decreases in the absence of mechanical stimulation (46), and protein breakdown transiently increases then diminishes during disuse (46); both of these responses are likely dependent ...

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