Disuse during acute hospitalization is linked to functional deficiencies, hospital readmission, impaired recovery, and increased mortality. Older adults are particularly vulnerable as functional (vascular and skeletal muscle mitochondrial dysfunction) and structural (loss in muscle mass and strength) deficits are present as a consequence of the aging process. In older adults, accelerated declines occur during disuse further depleting an already diminished physiological and functional reserve capacity. Currently, skeletal muscle-centered strategies to prevent atrophy and losses in strength are ineffective and the mechanism(s) contributing to accelerated losses are unknown, but appear to be linked to oxidative stress. Therefore, identifying the mechanism(s) and developing effective strategies to mitigate losses in vascular and skeletal muscle function, systems that are inextricably linked to mobility, disease progression, and health, is critical to delay the onset of disability and preserve the health of older adults. It is our central hypothesis that oxidative stress triggers the accelerated declines in vascular and skeletal muscle function during disuse. Two novel and fundamentally unique approaches to diminish oxidative stress are proposed including; 1) mitochondrial targeted antioxidants (MITO-AO;
Aim 1) and 2) the nuclear factor erythroid-2-like 2 (Nrf2) activator, PB125 (Aim 2). A total of 72 healthy older men and women (> 65 yrs.) will be block randomized to 3 groups; CONTROL, MITO-AO, and PB125. Five days of bed rest, a model of disuse mimicking acute hospitalization, will be used to evoke oxidative stress and losses in vascular and skeletal muscle function.
In Specific Aim 1, participants will receive MITO-AO (consisting of mitoquinone) during 5 days of bed rest. It is expected that MITO-AO will blunt the increase in oxidative stress by limiting mitochondrial-derived reactive oxygen species (ROS) production leading to preserved vascular and skeletal muscle function, thereby revealing a critical role of mitochondrial-derived ROS.
In Specific Aim 2, the novel Nrf2 activator, PB125, will be administered during 5 days of bed rest. It is expected that activation of Nrf2 with PB125 will restore the age-related dysfunction of the Nrf2 signaling pathway resulting in the induction endogenous antioxidant enzymes that will, in turn, maintain redox balance induced by disuse. The primary outcome measure for both aims is the assessment of vascular function as measured by passive leg movement (PLM). Secondary outcomes measures will assess the contributions of oxidative stress to the observed changes in vascular and skeletal muscle function before and after bed rest and will include direct measurements of free radicals, mitochondrial function and hydrogen peroxide production, markers of oxidative stress at the cellular, tissue, and systemic levels, changes in muscle mass and strength, and changes in muscle protein and gene expression that may be mechanistically linked to proteolysis and atrophy during disuse.
There is an epidemic of disuse in older hospitalized patients during which increased oxidative stress and accelerated losses in vascular and skeletal muscle function further diminish the already depleted physiological and functional reserve capacity of older individuals leading to impaired recovery, disability, and increased mortality. The proposed project will comprehensively examine two novel strategies, mitochondrial targeted antioxidants (MITO-AO) and the Nuclear Factor Erythroid-2-like 2 (Nrf2) activator, PB125, aimed at diminishing oxidative stress and thereby minimizing the negative impact of disuse. Mechanistic insight will be gained by examining how these strategies uniquely impact oxidative stress, the key for triggering the accelerated losses in vascular and skeletal muscle function during disuse.
