Unilateral hindlimb ischaemia-induced systemic inflammation is associated with non-ischaemic skeletal muscle inflammation.

ABSTRACT

Skeletal muscle atrophy and dysfunction commonly accompany cardiovascular diseases such as peripheral arterial disease and may be partially attributable to systemic inflammation. We sought to determine whether acute systemic inflammation in a model of hindlimb ischaemia (HLI) could affect skeletal muscle macrophage infiltration, fibre size, or capillarization, independent of the ischaemia. Eight-week-old C57BL/6 male mice underwent either Sham or HLI surgery, and were killed 1, 3, or 7 days post-surgery. Circulating inflammatory cytokine concentrations were measured, as well as immune cell infiltration and morphology of skeletal muscle from both limbs of HLI and Sham mice. In HLI compared with Sham mice at day 1, plasma interleukin-1ß levels were 216% higher (0.48 ± 0.10 vs. 0.15 ± 0.01 pg/µL, P = 0.005) and decreased by day 3. This was followed by increased macrophage presence in muscle from both ischaemic and non-ischaemic limbs of HLI mice by day 7 (7.3- and 2.3-fold greater than Sham, respectively, P < 0.0001). In HLI mice, muscle from the ischaemic limb had 21% lower fibre cross-sectional area than the non-ischaemic limb (724 ± 28 vs. 916 ± 46 µm2, P = 0.01), but the non-ischaemic limb of HLI mice was no different from Sham. This shows that HLI induces acute systemic inflammation accompanied by immune infiltration in both ischaemic and remote skeletal muscle; however, this did not induce skeletal muscle atrophy in remote muscle within the 7-day time course of this study. This effect of local skeletal muscle ischaemia on the inflammatory status of remote skeletal muscle may signal a priming of muscle for subsequent atrophy over a longer time course. HIGHLIGHTS What is the central question of this study? Does hindlimb ischaemia-induced inflammation cause acute immune, inflammatory and morphological alterations in remote non-ischaemic skeletal muscle? What is the main finding and its importance? Hindlimb ischaemia induced systemic inflammation with subsequent neutrophil and macrophage infiltration in both ischaemic and non-ischaemic skeletal muscle; however, morphological changes did not occur in non-ischaemic muscle within 7 days. These immune alterations may have functional implications that take longer than 7 days to manifest, and subsequent or prolonged systemic inflammation and immune infiltration of muscle could lead to morphological changes and functional decline.