Age-Dependent Effects of Losartan and Exercise on Skeletal Muscle Redox Balance and Protein Turnover in Mice

Aging is associated with impaired muscle protein turnover, oxidative stress, and functional decline. Both renin-angiotensin system (RAS) inhibition and exercise modulate redox balance and anabolic-catabolic signaling; however, how aging influences their effects under physiological conditions remains unclear.

Middle-aged (50 weeks) and old (72 weeks) female C57BL/6 mice were randomly assigned to control (C), losartan (L; RAS inhibitor), exercise (E), or combined losartan plus exercise (LE) groups for a four-month intervention. Exercise capacity, cardiac function, oxidative stress markers [thiobarbituric acid reactive substances (TBARS) and total antioxidant capacity (TAC)] in skeletal muscles, and key regulators of muscle protein turnover (Akt, mTOR, ERK1/2, Smad2, FoxO3a, and p38 MAPK) were evaluated. Two-way analysis of variance was used to determine whether age influences the effects of interventions.

Exercise training (E and LE) improved exercise capacity in both age groups. The combined LE intervention significantly enhanced cardiac systolic function compared to exercise alone. Losartan exerted age-dependent, opposite redox effects. In middle-aged mice, losartan increased TBARS and reduced TAC. Conversely, in old mice, losartan significantly reduced TBARS and increased TAC. Most protein turnover regulators (Akt, mTOR, ERK, FoxO3a, and p38 MAPK) remained unchanged by interventions, while Smad2 activation exhibited age-dependent patterns. Smad2 activation levels increased in middle-aged LE mice but were reduced by exercise in old mice.

While exercise is a robust intervention, losartan's efficacy is critically dependent on the animal's baseline oxidative status. These findings highlight the importance of considering age as a critical factor when designing pharmacological interventions for age-related muscle atrophy.