Assessing Age-Related Changes in Muscle Stem Cell Biochemistry

Researchers here discuss some of the results achieved in building the Human Skeletal Muscle Aging Atlas. Focusing on stem cells in muscle tissue, they find numerous changes in gene expression relating to inflammation and reduced activity. The chronic inflammation characteristic of aging, provoked by senescent cells and innate immune reactions to molecular damage, is known to be involved in many of the dysfunctions of aging. Loss of stem cell activity, and thus a reduced supply of daughter somatic cells to replace losses and repair damage, is one of those dysfunctions.

Skeletal muscle aging is a key contributor to age-related frailty and sarcopenia with substantial implications for global health. Here we profiled 90,902 single cells and 92,259 single nuclei from 17 donors to map the aging process in the adult human intercostal muscle, identifying cellular changes in each muscle compartment.

From our in-depth analysis, we identified aging mechanisms acting in parallel across different cell compartments. In the muscle stem cell (MuSC) compartment, we found downregulation of ribosome assembly resulting in decreased MuSC activation as well as upregulation of pro-inflammatory pathways, such as NF-κB, and increased expression of cytokines, such as CCL2. In the MF microenvironment, we found several cell types that expressed pro-inflammatory chemokines, such as CCL2, CCL3, and CCL4. These cytokines may mediate the recruitment of lymphoid cells into muscle and the pro-inflammatory environment of aged muscle. Moreover, our cross-species and cross-muscle integrated aging atlas highlights an overall downregulation in gene expression, an increase in inflammation and a decrease in pro-growth, repair, and innervation pathways. Pan-microenvironment upregulation of CCL2 with age was not recapitulated in mice, suggesting an interesting human-mouse distinction in orchestration of inflammation.

Our atlas also highlights an expansion of nuclei associated with the neuromuscular junction, which may reflect re-innervation, and outlines how the loss of fast-twitch myofibers is mitigated through regeneration and upregulation of fast-type markers in slow-twitch myofibers with age. Furthermore, we document the function of aging muscle microenvironment in immune cell attraction.



Is inflammaging caused by genetic errors both in somatic cells and in the immune cells themselves? They lose the perfect recognition of somatic cells both because the target changes and the program changes. Is this more or less what is going on?

Posted by: MattP at April 22nd, 2024 7:34 AM
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