Fig. 6. mTORC1 suppresses extracellular matrix (ECM) remodeling, promotes inflammation, and is involved in muscle responses to functional denervation.

a Coordinates of principal components (PC2–4) for gene expression data (TPM) collected in tibialis anterior (TA), triceps brachii (TRI), soleus (SOL), and gastrocnemius (GAS) from 10mCON and 30mCON mice. b Coordinates of PC1 and PC2 for gene expression data (TPM) generated from extensor digitorum longus (EDL) muscle of 3- and 9-month-old TSCmKO and littermate control mice. The numbers associated with the PCs indicate the fraction of the variance in gene expression in samples along the corresponding PC. Each dot corresponds to one muscle sample, from an individual animal. Linear regression analysis was used to compare slopes and intercepts. c Overlap of genes aligned with PC3 from a (natural aging) and PC1 from b (premature aging). A gene was considered aligned with a PC if the absolute value of the Pearson correlation coefficient between the expression of the gene and PC coordinates was ≥0.4, and the absolute value of the z score of the projection of the gene expression on a PC was ≥1.96. Red and blue numbers represent increasing and decreasing genes, respectively, while black numbers represent genes oppositely regulated between TSCmKO and sarcopenia data sets. d Top-ten DAVID gene ontology terms enriched (P < 0.01) for genes aligned to natural aging PC3 and the enrichment of these terms for genes aligned with premature aging PC1. e Heatmap of changes occurring during aging in the expression of genes aligned with natural aging PC3, i.e., common age-related gene-expression changes (30mCON/10mCON) in all four muscles, along with fold changes in these genes for 30mRM/30mCON, 9mTSCmKO/3mTSCmKO, and 9mTSCmKO/9mCON. Hierarchical clustering based on the Euclidean distance of these changes rendered 10 gene clusters, including three prominent clusters, now referred to as clusters 1, 2, and 3. Genes associated with clusters 1, 2, and 3 are listed. f Top-eight DAVID gene ontology terms enriched (P < 0.01) for gene clusters 1, 2, and 3, respectively. Enrichment significance threshold was set at P < 0.01 (gray and red dashed lines). Genes from clusters 1 to 3 contributing to the top enriched terms are colored. For TSCmKO data set n = 5 mice per group. For the sarcopenia data set, n = 6 mice per muscle per group, except for SOL 30mCON where one data point was removed due to a technical error. A modified Fisher’s exact test was used to determine significance.