Exercise training in frail older adults residing in nursing homes: Exploring the muscle-related mechanisms behind its positive effect on physical function

Abstract Frailty is characterised by reduced physiological reserves and an increased vulnerability to adverse outcomes such as physical function decline, dependency in basic activities of daily living and falls. Exercise is the most effective intervention to manage frailty, as it enhances the function and resilience of multiple physiological systems. However, the biological mechanisms through which exercise exerts such benefits are not fully understood. Evidence on the feasibility and effectiveness of exercise programs tailored to the most frail older adults is also limited. This thesis explores: I) the relationship between frailty pathophysiology, myokines, and physical function; and II) the feasibility and effectiveness of concurrent exercise (aerobic and resistance) interventions compared to usual care in nursing home residents. Four studies were conducted: a narrative review, a cross-sectional study (n= 59, mean age 82.7 years), a 12-week (n= 46, mean age 82.9 years) and a 12-month (n = 95, mean age 81.9 years) concurrent exercise trial. The review established a theoretical foundation linking impaired energy metabolism to frailty progression, emphasising the role of skeletal muscle as an endocrine organ. It also described how the concentration of myokines, such as myostatin (MSTN), responds to exercise, being involved in physiological processes that appear to improve systemic resilience in older adults. However, the evidence is limited. The cross- sectional study showed that higher serum MSTN levels were associated with lower odds of frailty and with better physical function. The 12-week concurrent training was feasible, improved physical performance and handgrip strength, and reduced MSTN levels in frail residents. When the same training was applied over 12 months (pragmatic trial), improvements in physical performance and handgrip strength were observed, with no changes in independence in basic activities of daily living or in the rate of falls. However, the usual care group showed a significant worsening in these outcomes, whereas the exercise group remained stable, suggesting a protective effect. Overall, this thesis supports the feasibility and effectiveness of concurrent exercise in improving physical function in NH residents, particularly among frail individuals. The findings also suggest that myokines, such as MSTN, may mediate these benefits, warranting further investigation.