Harnessing muscle-specific atrophy susceptibility to disentangle the mechanisms of disuse atrophy in human skeletal muscle

Skeletal muscles, which surround our bones, are crucial for movement. However, skeletal muscles are also important for the health of our whole body e.g. control of blood sugar (to prevent diabetes). The health of our muscles is directly linked to levels of physical (in)/activity. For example, physical inactivity causes our muscles to shrink in size and, if sustained, is linked to poor health outcomes. In contrast, exercise is linked with improved health. However, there are numerous situations where immobilization is enforced e.g. when recovering from a severe illness or operation, people often remain bedbound for days or even weeks. Similarly, after a fall or fracture, limbs may be immobilized to aid bone healing.

This proposal will investigate the underlying reasons for muscle wasting in response to disuse in humans, and explore the time-course of this (i.e. does most wasting occur in the first few days?) We will recruit 24 volunteers who will be assigned to one of two groups, who will undergo either 5 or 15 days of single leg immobilization (via a leg brace) with a study day before and after. During this study day, we will measure a number of factors relating to skeletal muscle and whole-body health to see how these have been impacted by immobilization (e.g. muscle building/ breaking down rates, muscle blood flow etc.). We will also look at these responses in two different muscles of the leg: one that has been shown to be much more prone to muscle wasting than the other. The idea behind this innovative approach, is to help us identify the key features regulating muscle loss, which should be more pronounced in "atrophy susceptible" muscle.

Taken together, this project could have groundbreaking implications for understanding muscle changes during periods of disuse, and associated health outcomes. Moreover, this project will form the basis for identifying optimal strategies (exercise, nutrition or drug-based) to counter the adverse effects of skeletal muscle disuse.

Skeletal muscles serve as the central node for locomotion and whole-body metabolic health. Muscle contraction in the form of exercise is well established to improve metabolic health and induce favorable physiological adaptations (e.g. muscle mass gains, mitochondrial biogenesis) and secondary health benefits (e.g. improved insulin sensitivity, reduced adiposity). In stark contrast to this, a loss of muscle contraction in the form of "disuse" (e.g. through casting immobilization or bed-rest, for example) has the opposite effect; causing muscle atrophy, associated functional decline and inducing muscle insulin resistance. There is however, a poor understanding of the metabolic and molecular regulation of disuse atrophy (DA) in humans. Herein I propose a clinical study to address a number of knowledge gaps in relation to the regulation of DA in humans. Recruiting two groups of subjects (total n=24) to distinct periods of (unilateral lower limb) immobilization, the temporal aspect of disuse atrophy will be explored. Moreover, I will take the highly novel approach of contrasting responses of "atrophy resistant" (i.e. tibialis anterior) with "atrophy susceptible" muscles (i.e. medial gastrocnemius) to immobilization. This unique study design will allow me to characterize how atrophy susceptibility is linked to the putative processes regulating DA i.e. muscle protein turnover, cell signaling, vascular adaptation and global gene expression - in the hope of determining true cause-effect relationships for the development of DA. These studies will shed light on the concept of atrophy resistance; identifying positive and negative regulators of muscle mass maintenance and afford us cause-effect relationships between metabolic and genomic changes and those of disuse atrophy, directly in humans. Furthermore, the molecular signatures generated may be employed as predictors of future intervention targets to mitigate disuse atrophy and associated health detriments.

In addition to academic beneficiaries this work will also benefit the wider public, the commercial private sector and charities. Academic beneficiaries will be the wider muscle biology/ physiology community via provision of innovative knowledge on: i) disuse adaptation in response to different temporal periods of immobilization, ii) the causes of atrophy resistance and susceptibility, and iii) the relationship between disuse atrophy and nutrient metabolism/ delivery. The wider public will eventually benefit from this work in the form of improved exercise and nutritional advice for those at risk of disuse atrophy, ultimately (it is hoped) decreasing healthcare expenditure. On this basis, within 10 years (should bona fide biomarkers of atrophy resistance arise from this work as anticipated) this could reduce public healthcare expenditure by providing more catered and informed healthcare. For example, were an individual with a more atrophy susceptible transcriptome be scheduled for surgery with an established period of post-operative immobilization, early pharmacological and/ or nutritional intervention could be implemented as a preventative measure. Therefore, this work could have a marked impact on provision of therapy in people undergoing enforced periods of reduced activity and/ or immobilization. Additionally, knowledge of the metabolic and molecular basis of temporal and muscle specific atrophy will generate a list of potential therapeutic targets (e.g. from pathways associated with muscle adaptation) which could positively impact conditions associated with disuse/ reduced use (e.g. sarcopenia, hip fracture patients). This could act to reduce the economic burden of a number of highly prevalent clinical situations, including older age within 10 years, giving time for rigorous substantiation work and clinical trials; perhaps even with drug repurposing options being explored. Importantly, as the PI is a member of the MRC-ARUK Centre for Musculoskeletal Ageing Research they are uniquely positioned to conduct BBSRC funded basic research and interact with those engaged in seeking evidence-based 'treatments' and understanding for improving muscle and whole body health across the lifespan. In this environment, the translational process may begin as soon as the end of the second year of this project and facilitate the cross-council prioritization of lifelong health and wellbeing research. The commercial private sector will benefit in the development and commercialization of innovative personalized healthcare approaches informed by the proposed mechanistic, metabolic and molecular work, and also by informatics work applied for as future funding i.e., to mine baseline blood and muscle samples to establish predictors of 'responder' status and, hopefully, assign appropriate atrophy prevention paradigms. These impacts will be felt within the third year as results of these immobilization periods are presented and published. Charities will also benefit in much the same way, particularly those charities that support increased quality of life in individuals with problems that involve muscle-linked metabolic decline such as obesity, frailty, loss of mobility and increased risk of falls (e.g., Research into Ageing, ARUK, Abbeyfield).