We have received a Research Council Norway (RCN) Grant for just under 9M NOK (1M USD)!
Project title: Does human skeletal muscle possess an epigenetic memory of wasting? Targeting UBR5 as a therapy for muscle wasting with age.
Primary and secondary objectives of the project: 1) We will discover if human skeletal muscle possesses an epigenetic memory of muscle wasting if muscle wasting is repeated. 2) We will test a muscle gene therapy targeting UBR5 during recovery from muscle wasting in aged animals, and assess if this protects the muscle from a second repeated muscle wasting encounter.
Project summary: In Norway, hip fracture caused by accidental falling, especially in winter weather conditions, 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.
Outcomes and impacts: 1) The newly proposed studies will be the first to determine whether human skeletal muscle possesses an epigenetic memory of earlier muscle wasting. 2) The experiments will be the first human and animal models to undertake repeated muscle wasting. The animal model will also refine and reduce the use of animals in muscle wasting research. 3) The research will be the first to use UBR5 RNAi and overexpressing vectors in muscle tissue specific gene therapy in aged animals. 4) The project will provide the first insight into muscle tissue gene therapy for repeated muscle wasting. Working towards a treatment protocol aimed at the recovery of muscle following the first encounter with atrophy. This would prevent the muscle from repeated falling and wasting injury. A logical and potential future treatment strategy for humans.