The Effects of Aging on Oxidative Stress in Type II Skeletal Muscles with Disuse

Skeletal muscles become smaller and weaker with aging and disuse (e.g., occurring with limb immobilization, bed rest). Although muscle dysfunction happens with aging and disuse, the target muscles are different. Type I muscles (low force production, slow contractile velocity) which play a major role in posture maintenance (such as standing) are more susceptible to the damage from muscle disuse. In contrast, type II muscles (high force production, fast contractile velocity) which are responsible for movement generation (such as ankle dorsiflexion during ambulation) are affected most by the aging process. One proposed mechanism underlying skeletal muscle dysfunction with aging and disuse is oxidative stress, a condition where the production of free radicals is greater than their elimination. My previous studies focused on type I muscles and revealed two important findings: (1) aging plays a significant role in the ability of the muscles to adapt such that the positive adaptation of the antioxidants with muscle disuse is compromised in aging muscles; (2) critical skeletal muscle proteins are targets of oxidative stress and show age-related accumulation of oxidative modification with disuse. Together, the findings suggest that the increased oxidative stress in type I muscles with disuse is better managed in adult muscles compared to aging muscles. In terms of muscle function, it has been reported that the detrimental effect of disuse on muscle strength is greater in aging muscles, especially when the muscles contract at high velocity. This finding implies that type II muscles which are responsible for high velocity of contraction are more vulnerable to the damage of muscle disuse in aging persons compared to adult persons. To date, it is unknown whether the disuse-related accumulation of oxidative stress and damage is greater in aging type II muscles compared to adult type II muscles. I hypothesize that the adaptations of antioxidants with disuse are compromised in aging type II muscles. Accordingly, the changes in the protein profile of myosin (the most abundant protein in skeletal muscles which is responsible for the production of muscle contraction) and other cytosolic proteins with muscle disuse are also dependent on the age of animals. To test the hypotheses stated above, I propose to conduct a two-factor experimental study using aging (adult and old rats) and muscle disuse animal models (hindlimb unloading for 0, 3, 7, 14 days) where the levels of antioxidants and protein profiles in type II muscles will be determined. I will use the combination of traditional methods (Western blot, enzyme assays) and proteomic techniques (mass spectrometry) to collect data. The data will be analyzed statistically using 2 way ANOVA and Tukey-Kramer Multiple Comparison Test. The proposed study is important because muscle disuse, a condition that the elderly are more likely to experience due to bed rest or orthopedic surgeries, results in muscle dysfunction, which often causes frailty and mobility disability of the elderly. I expect the results of the proposed study will not only increase the knowledge in the field of muscle biology but also provide the foundation for the future studies focused on the development of the treatment/prevention strategies during/before periods of muscle disuse.

Project ID:PC9902-2317
External Project ID:NSC99-2320-B182-001