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Skeletal Muscle Cell Atlas Reveals Age-Related Shifts in Gene Expression, Cell Types

NEW YORK – By putting together a cell atlas for skeletal tissue samples from younger and older adults, a team led by investigators in the UK and China has detected gene expression and cell type shifts associated with muscle aging.

The results, published in Nature Aging on Monday, highlight a potential role for inflammation and altered activity of muscle stem cell ribosomes in aging. In parallel, the cell atlas revealed ways that slow-twitch muscle fiber expression and nerve-muscle communication may shift to counterbalance some age-related decline.

"Our broad atlas highlights that muscle aging is more complex than we thought," co-first author Veronika Kedlian, a researcher at the Wellcome Sanger Institute, said in an email.

"While most aging changes are seen as harmful, some might actually be the body's way of trying to compensate or fight back," she explained. "This is, of course, crucial to tell apart for developing treatments as we need to leverage these mechanisms in a different way."

While it is known that skeletal muscle tends to decline with age, sometimes progressing to conditions such as sarcopenia that involve a loss of muscle strength and physical function, and an increase in frailty risk, Kedlian and her co-authors explained, the mechanisms and cell type dynamics contributing to muscle aging are not fully understood.

"Skeletal muscle aging is characterized by the loss of both muscle mass and strength, often leading to sarcopenia," they wrote. "This is a major contributory factor to falls and fractures in older adults, the second-leading cause of injury and deaths."

As part of an international effort known as the Human Cell Atlas, investigators at the Wellcome Sanger Institute, Sun Yat-sen University, and elsewhere turned to single-nucleus and single-cell RNA-seq to assess intercostal skeletal muscle biopsy samples. The biopsies were obtained from the Cambridge Biorepository for Translational Medicine, representing eight deceased donors between the ages of 20 and 40 years and nine samples from 60- to 75-year-old donors.

Across those samples, the researchers profiled gene expression in 92,259 individual nuclei and 90,902 single cells, providing muscle aging clues that they analyzed alongside single-cell or single-nucleus expression data for tens of thousands of single hindlimb muscle cells from five young mice and three elderly mice.

In addition to insights into cell types like muscle fiber cells, muscle stem cells, and cells of the muscle microenvironment, the team saw an aging-related decline in the activity of genes involved in ribosome production, or ribosome biogenesis in muscle stem cells, consistent with reduced muscle repair capabilities.

In addition, the researchers explained, their results revealed an age-related rise in the pro-inflammatory cytokine CCL2 in muscle stem cells and in non-muscle cell types such as vascular cells or fibroblasts, hinting at inflammatory and immune cell activity within aging skeletal muscle.

The investigators' analyses also pointed to altered gene expression profiles in slow-twitch muscle fibers, bringing them closer to expression patterns found in fast-twitch fibers as individuals aged. Likewise, they saw an uptick in fast-twitch muscle regeneration in older individuals, potentially helping to combat the known age-related loss in fast-twitch muscle fiber size and quantity.

"As we get older, we lose a specific type of muscle fiber (fast-twitch) while genes related to these fibers increase in another type (slow-twitch)," Kedlian said, noting that muscle fiber nuclei "have different states, and their changes with age don't always match those of the muscle fibers themselves."

Finally, the expression profiles revealed previously unappreciated activity in nuclei associated with neuromuscular junctions, the researchers reported, suggesting that there may be unrecognized mechanisms for cobbling communication back together between nerve and muscle cells as the nerve-muscle connections are increasingly lost with age.

Additional research is needed to further delineate such processes and explore possible strategies for treating the negative effects of muscle aging. In particular, Kedlian noted that the nuclei associated with nerve-muscle connections and the increased CCL2 expression profiles may offer "promising avenues for further research."

"With these new insights into healthy skeletal muscle aging, researchers all over the world can now explore ways to combat inflammation, boost muscle regeneration, preserve nerve connectivity, and more," co-corresponding author Sarah Teichmann, a Human Cell Atlas founder and researcher at the Wellcome Sanger Institute, said in a statement. "Discoveries from research like this have huge potential for developing therapeutic strategies that promote healthier aging for future generations."