The pro- and anti-inflammatory macrophages are associated with insulin sensitivity and skeletal muscle regeneration. Infiltrating macrophages in skeletal muscle during a period of physical inactivity and subsequent reloading/rehabilitation in older adults is unknown, but may provide insight into mechanisms related to the development of metabolic disease and changes in muscle cell size. The purpose of this study was to determine if skeletal muscle macrophage infiltration is modulated differently between young and older adults after bed rest and exercise rehabilitation and if these responses are related to muscle and insulin sensitivity changes. 14 young and 9 older adults underwent 5-days of bed rest followed by 8-weeks of lower limb eccentric exercise rehabilitation (REHAB). Dual-energy X-ray absorptiometry, magnetic resonance imaging and myofiber analysis were used to identify muscle morphology and CLIX-IR and CLIX-β were used to assess insulin sensitivity. Skeletal muscle macrophages, CD68 (pan), CD11b (M1), CD163 (M2), CD206 (M2), were characterized using immunohistochemistry and gene expression. Insulin sensitivity, independent of age, decreased ~38% following bed rest and was restored following REHAB. We found robust age-related differences in muscle atrophy during bed rest, yet older and younger adults equally hypertrophied during REHAB. Interestingly, there were age-related differences in macrophage content (CD68CD11b and CD68CD11b cells) but both young and old similarly increased macrophages with REHAB. Satellite cell changes during rehab corresponded to macrophage content changes. Muscle tissue resident macrophages and gene expression, were not associated with changes in insulin sensitivity following bed rest and REHAB. These data suggest that muscle macrophages are modulated as a result of exercise rehabilitation following bed rest and may more associated with muscle regrowth/hypertrophy rather than insulin sensitivity in young or older adults. This trial was registered at clinicaltrials.gov as NCT01669590.

Impaired recovery of aged muscle following a disuse event is an unresolved issue facing the older adult population. Although investigations in young animals have suggested that rapid regrowth of skeletal muscle following a disuse event entails a coordinated involvement of skeletal muscle macrophages, this phenomenon has not yet been thoroughly tested as an explanation for impaired muscle recovery in aging. To examine this hypothesis, young (4–5 mo) and old (24–26 mo) male mice were examined as controls following 2 wk of hindlimb unloading (HU) and following 4 (RL4) and 7 (RL7) days of reloading after HU. Muscles were harvested to assess muscle weight, myofiber-specifc cross-sectional area, and skeletal muscle macrophages via immunofluorescence. Flow cytometry was used on gastrocnemius and soleus muscle (at RL4) single-cell suspensions to immunophenotype skeletal muscle macrophages. Our data demonstrated impaired muscle regrowth in aged compared with young mice following disuse, which was characterized by divergent muscle macrophage polarization patterns and muscle-specifc macrophage abundance. During reloading, young mice exhibited the classical increase in M1-like (MHC II+CD206−) macrophages that preceeded the increase in percentage of M2-like macrophages (MHC II−CD206+); however, old mice did not demonstrate this pattern. Also, at RL4, the soleus demonstrated reduced macrophage abundance with aging. Together, these data suggest that dysregulated macrophage phenotype patterns in aged muscle during recovery from disuse may be related to impaired muscle growth. Further investigation is needed to determine whether the dysregulated macrophage response in the old during regrowth from disuse is related to a reduced ability to recruit or activate specific immune cells.

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Purpose of reviewType 2 diabetes mellitus (T2D) confers a greater risk of skeletal fragility and fracture. Whether prediabetes is detrimental to bone health is uncertain.Recent findingsWe summarize the current data on the associations of prediabetes with bone turnover, bone mineral density, bone quality, bone material properties and fracture risk.SummaryIn cross-sectional studies, prediabetes was associated with lower bone turnover and worse trabecular bone quality. A longitudinal analysis showed that larger increase in insulin resistance (in the absence of T2D) correlated with faster bone loss. Future research to examine the longitudinal associations of prediabetes with bone health parameters is warranted.