FRIPRO-Fri prosjektstøtte

In Norway, hip fracture caused by accidental falling is associated with poor health and earlier death. The deterioration of muscle mass as we grow older contributes to weakness and increases the chances of accidental falling injury. Once an elderly person is injured, a vicious cycle occurs whereby that individual is immobile and further muscle is lost. This then increases the chances of having a repeated falling injury due to increased muscle weakness and frailty. Muscle weakness can severely affect an elderly person’s ability to undertake simple daily tasks and their quality of life, and frailty is a huge economic cost to European health systems. This research is investigating the molecular mechanisms of repeated muscle wasting in humans. Our research has already shown that muscle has a memory of growth at the DNA level after repeated exercise. In the present project so far, preliminary data analysis demonstrates that human muscle and aged rat muscle has a memory of wasting after repeated muscle wasting stimuli. Human muscle recovers quite well from a first period of muscle wasting, however certain muscle groups in young humans and in aged muscle seem more susceptible to further loss with repeated atrophy. In humans we discover oxidative phosphorylation, electron transport chain, NAD/NADH processes and mitochondrial function genes are enriched as down-regulated after atrophy and repeated atrophy. With some genes in these pathways not recovering from wasting and/or become more susceptible to repeated muscle wasting in humans. We are currently overlapping methylome and transcriptome data to identify whether epigenetics is important in these genes possessing a memory at the transcriptional level. Furthermore, we have undertaken muscle tissue gene therapy that alters levels of UBR5 in skeletal muscle of aged animals during recovery from a muscle wasting encounter to see if this treatment prevents repeated muscle wasting. We are currently analysing this data and will provide an update in the next project report.

In Norway, hip fracture caused by accidental falling is associated with poor health and earlier death. The deterioration of muscle mass as we grow older contributes to weakness and increases the chances of accidental falling injury. Once an elderly person is injured, a vicious cycle occurs whereby that individual is immobile and further muscle is lost. This then increases the chances of having a repeated falling injury due to increased muscle weakness and frailty. Muscle weakness can severely affect an elderly person’s ability to undertake simple daily tasks and their quality of life, and frailty is a huge economic cost to European health systems. This research will investigate the molecular mechanisms of repeated muscle wasting in humans. Our research has already shown that muscle has a ‘memory’ of growth at the DNA level after repeated exercise. We therefore believe muscle may also possess a DNA memory of repeated muscle wasting, and this belief will be tested in this research project. We also know that a gene called UBR5 is involved in muscle memory, an increase in muscle size and improving recovery from muscle wasting. Therefore, in this project we will undertake muscle tissue gene therapy that alters levels of UBR5 in skeletal muscle of aged animals during recovery from a muscle wasting encounter. We will then assess the muscle after a second muscle wasting event to see if this treatment prevents repeated muscle wasting. Because a falling injury and muscle wasting is an unpredictable event in humans, the implementation of a muscle therapy during recovery from a first muscle wasting event would be an effective treatment strategy to protect the muscle from later muscle wasting if another fall occurred. Overall, this research project will determine if this muscle therapy could improve muscle recovery from wasting and prevent repeated wasting.