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Clinical Trial
. 2018 Nov;596(21):5217-5236.
doi: 10.1113/JP276798. Epub 2018 Oct 9.

Skeletal muscle ceramides and relationship with insulin sensitivity after 2 weeks of simulated sedentary behaviour and recovery in healthy older adults

Paul T Reidy  1 , Alec I McKenzie  1 , Ziad Mahmassani  1 , Vincent R Morrow  1 , Nikol M Yonemura  1 , Paul N Hopkins  2 , Robin L Marcus  1 , Matthew T Rondina  3 , Yu Kuei Lin  4 , Micah J Drummond  1
Affiliations
Clinical Trial

Skeletal muscle ceramides and relationship with insulin sensitivity after 2 weeks of simulated sedentary behaviour and recovery in healthy older adults

Paul T Reidy et al. J Physiol. 2018 Nov.

Abstract

Key points: Insulin sensitivity (as determined by a hyperinsulinaemic-euglyceamic clamp) decreased 15% after reduced activity. Despite not fully returning to baseline physical activity levels, insulin sensitivity unexpectedly, rebounded above that recorded before 2 weeks of reduced physical activity by 14% after the recovery period. Changes in insulin sensitivity in response to reduced activity were primarily driven by men but, not women. There were modest changes in ceramides (nuclear/myofibrillar fraction and serum) following reduced activity and recovery but, in the absence of major changes to body composition (i.e. fat mass), ceramides were not related to changes in inactivity-induced insulin sensitivity in healthy older adults.

Abstract: Older adults are at risk of physical inactivity as they encounter debilitating life events. It is not known how insulin sensitivity is affected by modest short-term physical inactivity and recovery in healthy older adults, nor how insulin sensitivity is related to changes in serum and muscle ceramide content. Healthy older adults (aged 64-82 years, five females, seven males) were assessed before (PRE), after 2 weeks of reduced physical activity (RA) and following 2 weeks of recovery (REC). Insulin sensitivity (hyperinsulinaemic-euglyceamic clamp), lean mass, muscle function, skeletal muscle subfraction, fibre-specific, and serum ceramide content and indices of skeletal muscle inflammation were assessed. Insulin sensitivity decreased by 15 ± 6% at RA (driven by men) but rebounded above PRE by 14 ± 5% at REC. Mid-plantar flexor muscle area and leg strength decreased with RA, although only muscle size returned to baseline levels following REC. Body fat did not change and only minimal changes in muscle inflammation were noted across the intervention. Serum and intramuscular ceramides (nuclear/myofibrillar fraction) were modestly increased at RA and REC. However, ceramides were not related to changes in inactivity-induced insulin sensitivity in healthy older adults. Short-term inactivity induced insulin resistance in older adults in the absence of significant changes in body composition (i.e. fat mass) are not related to changes in ceramides.

Keywords: aging; metabolism; physical inactivity; reduced activity.

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Figures

Figure 1
Figure 1. Experimental design and step counts
A, experimental design for the 2‐week RA and REC study. B, daily step counts in healthy older adults (n = 12) at baseline (PRE), after the 2 week RA and after normal ambulatory REC periods. Percentage change, from PRE, of step counts (inset). *Different from PRE (P < 0.05). #Different from RA (P < 0.05). Data are the mean ± SEM.
Figure 2
Figure 2. Insulin sensitivity
Insulin sensitivity (GIR; mg kg−1 FFM min−1) in healthy older adults at PRE, following 2 weeks of RA and then 2 weeks of REC to normal activity pooled (A) and by sex (B). Percentage changes (PRE to RA, PRE to REC and RA to REC) in glucose infusion rate (GIR; mg kg−1 FFM min−1) in healthy older adults by sex (C). at RA and REC. * P < 0.05, ∧ P = 0.052, difference from 0; #P < 0.05 sex difference; &P < 0.05 vs. REC; %P < 0.05 vs. PRE and REC; $P < 0.05 vs. RA and REC. Data are the mean ± SEM.
Figure 3
Figure 3. Muscle and myofiber ceramide and immunoblotting
Vastus lateralis myofibre muscle cross‐sectional area, myofibre type‐specific ceramide content and total and species‐specific ceramide content at baseline (PRE), and at RA7, RA14 and REC, in healthy older adults (n = 12). Muscle cross‐sections are immunofluorecent analysis of MHC IIa positive and negative (MHC I) myofibres for cross‐sectional area (A) and ceramide intensity (B). A representative image of sections and immunofluorescence staining is shown (C). Basal changes (D, F and H) in intramuscular ceramide content from PRE to RA (D), RA to REC (F) and PRE to REC (H). Insulin stimulated changes (E, G and I) in ceramide content at PRE (E), RA (G) and REC (I). 100% is the reference value. Vastus lateralis myofibre immunoblotting of TLR4 (J and K), phospho‐JNK (Thr183/Tyr185)/JNK (L and M), phospho‐AKT (Ser473)/AKT (N and O), IκBα (P and Q) and SPT2 (R and S), as well as phospho‐p38 (Thr180/Tyr182)/p38 (T and U), during the 2 week RA and after ambulatory REC periods as the fold change from PRE baseline (J, L, N, P, R and T), and at RA7, RA14 and REC, and the fold change in response to insulin stimulation (K, M, O, Q, S and U) at PRE, RA14 and REC in healthy older adults (n = 12). Example immunoblotting images are shown (M). Data are the mean ± SEM. * P < 0.05; %P < 0.10. Significant change vs. comparator. Comparator (PRE, RA or REC) set at 1 or 100%. [Color figure can be viewed at http://wileyonlinelibrary.com]
Figure 4
Figure 4. Skeletal muscle subfraction lipid intermediates
Skeletal muscle mitochondrial/reticulum/plasma membrane, nuclear/myofibrillar and cytoplasmic sphinaganine (A), sphingosine (B), sphingosine‐1‐phosphate (S1P) (C), ceramide (D), dihydroceramide (E), glucosylceramide (F), sphingomyelin (G) and diacylglycerol (H) totals at PRE, RA and REC in healthy older adults. Skeletal muscle mitochondrial/reticulum/plasma membrane (I), nuclear/myofibrillar (J) and cytoplasmic (K) ceramide species at PRE, RA and REC in healthy older adults. Skeletal muscle mitochondrial/reticulum/plasma membrane, nuclear/myofibrillar and cytoplasmic phosphatidylcholine (L) and representative immunoblotting image of the fractionation (M). Data are the mean ± SEM. * P < 0.05 PRE vs. RA; #P < 0.05 PRE vs. REC, %P < 0.10.
Figure 5
Figure 5. Skeletal muscle subfraction diacylglycerol
Skeletal muscle subfraction [Mito (A); Nuclear (B); Cyto (C)] diacylglycerol at PRE, RA and REC in healthy older adults. Data are the mean ± SEM. * P < 0.05 PRE vs. RA, #P < 0.05 PRE vs. REC, ∧ P < 0.05 RA vs. REC, %P < 0.10.
Figure 6
Figure 6. Skeletal muscle subfraction and serum sphingolipids
Skeletal muscle subfraction (A, B, C, E, F, G, I, J and K) and serum (D, H and L) dihydroceramide (A, B, C and D), sphingomyelin (E, F, G and H) and glucosylceramide (I, J, K and L) at PRE, RA and REC in healthy older adults. Data are the mean ± SEM. * P < 0.05 PRE vs. RA, #P < 0.05 PRE vs. REC, ∧ P < 0.05 RA vs. REC, %P < 0.10.
Figure 7
Figure 7. Serum sphingolipids and sex‐specific ceramide changes
Serum sphingolipid totals (A) at PRE, RA and REC in healthy older adults. Serum ceramide species (B) at PRE, RA and REC in healthy older adults. Sex‐specific baseline changes from PRE to RA (presented as RA as % of PRE) in serum ceramide species (C) in healthy older adults. Data are the mean ± SEM. * P < 0.05 PRE vs. RA; #P < 0.05 PRE vs. REC; ∧ P < 0.05 sex difference. %P < 0.10.
Figure 8
Figure 8. Associations between ceramide and insulin sensitivity
Correlation analysis to test the association between the change in insulin sensitivity during physical inactivity (GIR % change from PRE to RA) and the change in ceramides (ceramide 16:0. 18:0 and total) implicated in skeletal muscle insulin resistance in serum and skeletal muscle homogenate and subfraction (mitochondrial/endoplasmic reticulum/plasma membrane, nuclear/myofibrillar and cytoplasmic enriched subfractions) from healthy older adults.
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