Research Paper Volume 12, Issue 20 pp 20001—20023

Systemic overexpression of C-C motif chemokine ligand 2 promotes metabolic dysregulation and premature death in mice with accelerated aging

Figure 3. The impact of Ccl2 overexpression on the metabolic pathways associated with energy and 1-C metabolism. Metabolomic analysis of skeletal muscle from progeroid mice with (LMNAG609G/+;CGCCL2+/-) or without (LMNAG609G/+) increased Ccl2 levels revealed the metabolic impact of Ccl2 in accelerated aging. (A) From left to right, partial least square discriminant analysis (PLSDA), heatmap with hierarchical clustering and random forest analysis indicating that Ccl2 drove changes in energy and 1-C metabolism in the quadriceps muscles of the genetically modified mice. The levels of metabolites were distinct in both strains, and the variables of highest importance, according to the projection scores, were glucose, citrate, SAH and methionine. (B) Comparison of the levels of metabolite abundance from glycolysis and the CAC cycle in the quadriceps muscles were assessed by fold changes, as indicated in the legend, suggesting that Ccl2 decreased mitochondrial oxidative metabolism. (C) Dysregulation in the methionine cycle was, at least partially, the cause of the increased DNA methylcytosine levels in the LMNAG609G/+;CGCCL2+/- mice with respect to the controls and LMNAG609G/+ mice. Values are shown as the means ± SEM; ap< 0.05 with respect to the wild-type mice and b p<0.05 with respect to the LMNAG609G/+ mice, according to the Mann–Whitney U tests.