Longevity Protein Found to Reduce Scarring After Muscle Injury in Mice

Scientists at the University of Pittsburgh have produced a comprehensive roadmap of muscle aging that could be used to find treatments that prevent decline in muscle mobility and function. The team also found that longevity protein Klotho reduced muscle scarring after injury. The study was published today in eLife.

First, the team characterized and compared changes in the structure, function and gene activity in skeletal muscle across the lifespan in mice. They grouped mice into four age categories—young, middle-aged, old and oldest-old—and looked at muscle weight, type of muscle fibers, whether the muscles had accumulated fat, and skeletal muscle function. Although old mice displayed mild sarcopenia, the common clinical features of sarcopenia were only present in the oldest-old mice.

Next, they looked at changes in muscle gene activity and found a progressive disruption in genes known to be associated with the hallmarks of aging from the young to the oldest-old mice. "To date, most studies in skeletal muscle have focused on the identification of specific pathways that are associated with sarcopenia to identify a molecular mechanism linked to the condition," explains co-first author Sruthi Sivakumar. "We employed an integrative approach, where we created a network by converting gene expression levels to protein-protein interactions, and then we studied how this interaction network changed over time."

From this network, the team determined the network entropy of the muscle cells as a means to estimate the loss of molecular order within the system over time. They found the greatest difference in order between the young and old age groups (at which point it reached maximal entropy), with little difference between the old and oldest-old mice. Additionally, when they looked at human muscle gene data from different age groups, they saw that entropy reached its lowest level in the fourth decade of life, after which time entropy escalated. Next, they looked at whether administering Klotho to mice would have beneficial effects on the muscle healing after injury. They found that applying Klotho reduced scarring and increased structures associated with force production in the animals. 

Further investigation showed that Klotho affected genes associated with the hallmarks of aging in all age groups, but that the oldest-old mice showed a dysregulated gene response. "Our data suggest that treatment with Klotho may be more effective in slowing the progression of sarcopenia at an earlier time point, rather than rescuing advanced age-related disease, by which time the gene responses seem to be more random," concludes senior author Fabrisia Ambrosio.