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bioRxiv · 10.1101/2021.05.17.444371

Skeletal Muscle Transcriptome Alterations Related to Physical Function Decline in Older Mice

Graber, T. G.·Maroto, R.·Thompson, J.·Widen, S.·Man, Z.·Pajski, M. L.·Rasmussen, B. B.
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Abstract

One inevitable consequence of aging is the gradual deterioration of physical function and exercise capacity, driven in part by the adverse effect of age on muscle tissue. Our primary purpose was to determine the relationship between patterns of gene expression in skeletal muscle and this loss of physical function. We hypothesized that some genes changing expression with age would correlate with functional decline, or conversely with preservation of function. Male C57BL/6 mice (6-months old, 6m, 24-months, 24m, and 28+-months, 28m; all n=8) were tested for physical ability using a comprehensive functional assessment battery (CFAB). CFAB is a composite scoring system comprised of five functional tests: rotarod (overall motor function), grip strength (fore-limb strength), inverted cling (4-limb strength/endurance), voluntary wheel running (activity rate/volitional exercise), and treadmill (endurance). We then extracted total RNA from the tibialis anterior muscle, analyzed with Next Generation Sequencing RNAseq to determine differential gene expression during aging, and compared these changes to physical function. Aging resulted in gene expression differences >[boxv]1.0[boxv] log2 fold change (multiple comparison adjusted p<0.05) in 219 genes in the 24m and in 6587 genes in the 28m. Linear regression with CFAB determined 253 differentially expressed genes strongly associated (R>0.70) with functional status in the 28m, and 22 genes in the 24m. We conclude that specific age-related transcriptomic changes are associated with declines in physical function, providing mechanistic clues. Future work will establish the underlying cellular mechanisms and the physiological relevance of these genes to age-related loss of physical function. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=96 SRC="FIGDIR/small/444371v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@ad7362org.highwire.dtl.DTLVardef@17267e7org.highwire.dtl.DTLVardef@38600org.highwire.dtl.DTLVardef@15283a7_HPS_FORMAT_FIGEXP M_FIG C_FIG RNA sequencing of skeletal muscle from young and old mice were compared to physical function status obtained by performing a comprehensive functional assessment battery of tests. Between adulthood (6-months) and older age (28-months), 6707 genes were differentially expressed with 253 of these genes being significantly associated with physical function. Specific age-related changes to the skeletal muscle transcriptome are associated with a decline in physical function.

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Graber, T. G., Maroto, R., Thompson, J., Widen, S., Man, Z., Pajski, M. L., Rasmussen, B. B.. 2021-05-17. Skeletal Muscle Transcriptome Alterations Related to Physical Function Decline in Older Mice. https://doi.org/10.1101/2021.05.17.444371

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