Processes of muscle-aging and physical weakness in females and males

Summary

The overall aim of this thesis, divided into three specific aims, was to gain insight into the processes of muscle aging and physical weakness in males and females. The first aim was to map which processes are associated with muscle aging and physical weakness in females and males separately. For this, in chapter 2, we compared old to young humans for each sex and showed that sex differences in the processes linked to muscle aging are minimal. In fact, the same processes are associated with muscle aging in both sexes, though their ranking differs between males and females. Next, in chapter 3, we separated the older participants based on physical function into the fittest and weakest groups. In contrast to muscle aging, the processes linked to physical weakness were highly sex-specific. Strikingly, genes associated with physical weakness were not necessarily associated with muscle aging, suggesting that physical weakness is not just a continuum of aging. The second aim was to identify blood-based biomarkers correlating with physical weakness in older adults, in the early stages of frailty. In chapter 4, we predicted which circulating proteins correlate with physical function in fit and pre-frail older adults, based on their muscle transcriptome profile. We successfully validated four sex-specific proteins that correlate with physical function. The third aim was to test the translatability of different mouse models for human muscle aging. In chapter 5, we mapped phenotypical changes occurring during natural aging in male and female mice, and the processes associated with muscle aging at various time points. These processes were then compared with those found in chapter 2 to assess how well mice model human muscle aging, including sex differences. In chapter 6, we used additional mouse models beyond naturally aged mice, including those exposed to food restriction and unilateral immobilization. We again mapped phenotypical changes and molecular processes associated with muscle atrophy and compared them to those linked with human muscle aging. Interestingly, the combination of food restriction and immobilization produced the largest overlap in pathways with human muscle aging. In chapter 7, we tested this mouse model with salbutamol treatment, which is known to be effective in humans. As expected, salbutamol ameliorated muscle atrophy in this model, but not in the immobilized hindpaw. Strikingly, we also showed that salbutamol is not as effective in humans during immobilization, mirroring our findings in the mouse model.