T2 , T1ρ and TRAFF4 detect early regenerative changes in mouse ischemic skeletal muscle.

The identification of areas with regenerative potential in ischemic tissues would allow the targeting of treatments supporting tissue recovery. The regeneration process involves the activation of several cellular and molecular responses which could be detected using magnetic resonance imaging (MRI). However, to date, magnetic resonance (MR) relaxation parameters have received little attention in the diagnosis and follow-up of limb ischemia. The purpose of this study was to evaluate the feasibility of different MRI relaxation and diffusion tensor imaging parameters in the detection of areas showing early signs of regeneration in ischemic mouse skeletal muscles. T2 and T1ρ relaxation time constants, together with TRAFFn , T1 and diffusion tensor imaging, were evaluated to differentiate areas of regeneration in a mouse hind limb ischemia model before and 0, 1, 4, 7, 14 and 30 days after ischemia. All the measured relaxation times were longer in the areas of early regeneration compared with normal muscle tissue. The relaxation times increased after ischemia in the ischemic muscles, reaching a maximum at 4-7 days after occlusion, coinciding with the appearance of early signs of regeneration. Fractional anisotropy decreased significantly (p < 0.05) on days 1-4, whereas mean diffusivity, λ1 and λ2 decreased later, starting at day 7 after ischemia compared with the pre-operational time point. The percentages of areas with different tissue morphologies were determined based on histological analysis of the ischemic muscle cross-sections, and correlations between the percentages obtained and different relaxation times were calculated. The highest correlation between relaxation times and histology was achieved with T2 , T1ρ and TRAFF4 (R2 = 0.96, R2 = 0.92 and R2 = 0.84, respectively, p < 0.01). Early regenerative changes were visible using T2 , T1ρ and TRAFF4 MR relaxation time constants in skeletal muscle after ischemia. These markers could potentially be used for the identification of targets for therapies supporting muscle regeneration after ischemic injury.