JAL | Free Full-Text | Skeletal Muscle Transcriptome Alterations Related to Declining Physical Function in Older Mice

JAL | Free Full-Text | Skeletal Muscle Transcriptome Alterations Related to Declining Physical Function in Older Mice

4.2. Regressions of DEGs with CFAB

We primarily focused our attention on the changes that occurred in the transcriptome between the adults (6m) and the oldest group (28m). This was because the alterations in gene expression were most extreme at the advanced age (several more DEGs and several more DEGs strongly associated with CFAB), and we knew from previous work that the most profound changes in function, muscle health, and contractile ability occur at the older ages in mice [9,10,13]. See the datasets in the Online Supplemental Data Tables S10–S21 for more details.
Regression analysis of the 6m–28m determined there were 704 DEGs with at least a moderate (R ≥ |0.50|) correlation with physical ability (CFAB score); of these, 372 were strongly associated with CFAB (R ≥ |0.70|). Of these strongly associated genes, 239 were positively associated and 133 were negatively associated with CFAB. Of the genes that were positively associated, all were downregulated. Of the genes that were negatively associated, all were upregulated. Table 4 lists the top (by |R|) age-regulated genes associated with physical function in the 28m group (see Table S10 for all R > |0.70|).
The different determinants of CFAB (VWR, Grip, Inverted Cling, Rotarod, and Treadmill) in the 6m–28m were regressed in the same way as CFAB (See Tables S11–S15). Notably, out of the top 71 DEGs correlated with CFAB (|R| > 0.80), 35 of them are also in the top 30 DEGs (by |R|) of the determinants (see Table S16). However, 11 of the top 30 (by |R|) DEGs in the CFAB list do not appear in the top lists of the determinants. For example, the top DEG on the CFAB list, Dclk3 (Doublecortin like kinase 3, R = 0.899), was not in the top 30 in any of the determinant lists. Interestingly, VWR, Grip Test, and Inverted Cling contain the most top CFAB correlates. However, the VWR top DEG, Necab1 (N-terminal EF-hand calcium-binding proteins 1, R = 0.791), and the only VWR DEG with |R| > 0.70, was ranked at #237 on the CFAB list (R = 0.741).
In contrast, of the 6m–24m DEGs, regression analysis determined that there were only 55 genes with at least a moderate (R ≥ |0.50|) correlation with physical ability (CFAB score); of these, only 35 were strongly associated (all R Table S17 for details). The different determinants of CFAB (VWR, Grip, Inverted Cling, Rotarod, and Treadmill) were regressed with the age-associated DEGs in the 6m–24m group (See Tables S18–S22). Notably, only inverted cling and grip had any DEGs with |R| ≥ 0.70, 24 and 13, respectively (see Tables S19 and S20 for details).
In addition, we regressed the TA muscle mass (dependent variable) with the DEGS of both sets (for details see 6m–28m in Table S23 and 6m–24m in Table S24) and found that there were 595 DEGs with |R| ≥ 0.70 in the 6m–28m group, while there were only 3 in the 6m–24m group: Ak4 (R = −0.76, log2fc 1.48), Erc2 (R = −0.72, log2fc 3.41), and Car3 (R = 0.697, log2fc 1.05). Notably, in the 6m–28m analysis, all three were also on the list: Ak4 (28m, ranked #164, R = −0.839, log2fc 1.08), Erc2 (28m, #212, R = −0.824, log2fc 3.54), and Car3 (28m, #28, R = −0.900, log2fc 1.32).

There are far more DEGs at the older age (6m–28m) that might have a role in functional loss or are potentially involved in the regulation of muscle mass. More than 10-fold DEGs were identified to be strongly associated with function in the 6m–28m group (372) than the 6m–24m (35). Furthermore, different DEGs were among the top |R| values in the two groups, and there were different |R| values for the same DEGs in the two analyses, potentially indicating that some genes can play a more significant role in the decline of physical function depending upon the age of the mouse.

Furthermore, using the gene set from Table S10, we ran ChEA via Enrichr, and the resulting transcription factors (48 significant terms were returned) that overlap (padj Table S25. The transcription factors with the highest combined scores included WT1, MTF2, CEBPD, SUZ12, SOX9, TP53, YAP1, ZNF217, ESR1, and DROSHA (48.2, 26.5, 25.5, 24.5, 21.6, 21.2, 18.9, 18.9, 18.6, and 18.2, respectively). Interestingly, CEBPD is a transcription factor DEG that we found to have reduced expression with age (log2fc −1.025), and that is strongly associated with CFAB (R = −0.792).

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