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The aim of this study was to determine whether whole body periodic acceleration (pGz) could improve muscle recovery after unaccustomed eccentric exercise (EE).Downhill treadmill running was used to elicit EE-induced muscle damage in mice, and pGz treatment (480 cycles per minute, 1 h·d−1) was applied daily for 10 d after the initial EE bout (day 0). Every 2 d during the pGz treatment course starting at day 0, we 1) assessed intracellular Ca2+ and Na+ concentrations and membrane potential (as indicators of intracellular ion dysfunction) in vivo in gastrocnemius muscle from anesthetized animals and 2) quantified creatine kinase (CK), tumor necrosis factor α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6), and interleukin-10 (IL-10) concentrations in plasma or muscle lysates (as indicators of muscle damage and inflammation).EE significantly increased intracellular Ca2+ and Na+, CK, TNF-α, MCP-1, IL-6, and IL-10, all of which peaked on day 2 with the exception of IL-10 and declined slowly over 10 d of recovery. pGz treatment after the EE bout mitigated ion dyshomeostasis and expedited recuperation to control values after 6 d of treatment. pGz treatment also accelerated the normalization of CK, TNF-α, MCP-1, and IL-6 while further increasing IL-10 concentrations. The nitric oxide synthase inhibitor L-NG-nitroarginine methyl ester, administered in drinking water before and maintained throughout the treatment course, was sufficient to abrogate the salutary effects of pGz after EE.The present study demonstrates whole body periodic acceleration as an effective therapeutic strategy to accelerate muscle recovery after EE-induced skeletal muscle injury, as indicated by a faster normalization of all the studied parameters.