Background Mechanisms underlying physical inactivity‐induced insulin resistance are not well understood. In addition to a role in muscle repair, immune cell populations such as macrophages may regulate insulin sensitivity. Aim The aim of this study was to examine if the dynamic changes in insulin sensitivity during and after recovery from reduced physical activity corresponded to changes in skeletal muscle macrophages. Methods In this prospective clinical study, we collected muscle biopsies from healthy older adults (70 ± 2 years, n = 12) before and during a hyperinsulinaemic‐euglycaemic clamp and this occurred before (PRE) and after 2‐week reduced physical activity (RA), and following 2‐week of recovery (REC). Insulin sensitivity (hyperinsulinaemic‐euglycaemic clamp), skeletal muscle mRNA expression of inflammatory markers, and immunofluorescent quantification of skeletal muscle macrophages, myofibre‐specific satellite cell and capillary content were assessed. Results Insulin sensitivity was decreased following reduced activity and rebounded following recovery above PRE levels. We observed an increase (P < 0.01) in muscle macrophages (CD68+CD206+: 190 [55, 324]; CD11b+CD206+: 117 [28, 205]% change from PRE) and CD68 (2.4 [1.4, 3.4]‐fold) and CCL2 (1.9 [1.3, 2.5]‐fold) mRNA following RA concurrent with increased (P < 0.03) satellite cells (55 [6, 104]%) in slow‐twitch myofibres. Moreover, the distance of satellite cells to the nearest capillary was increased 7.7 (1.7, 13.7) µm in fast‐twitch myofibres at RA (P = 0.007). Changes in macrophages were positively associated with increased insulin sensitivity following RA (R > 0.57, P < 0.05). Conclusion These findings suggested that a dynamic response of skeletal muscle macrophages following acute changes in physical activity in healthy older adults is related to insulin sensitivity.

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