Losartan improves measures of activity, inflammation, and oxidative stress in older mice

Abstract

Sarcopenia is an age-related decline in skeletal muscle mass and function that is multifactorial in etiology. Age-related changes in the renin-angiotensin system (RAS), increased oxidative stress, and chronic inflammation likely all contribute to its development. Losartan, an angiotensin II type I receptor blocker (ARB) decreases RAS activity and likely influences oxidative stress and inflammation. Given this, we hypothesized that losartan would improve activity levels and parameters related to inflammation and oxidative stress in older mice. We sought to test this hypothesis by comparing functional and molecular parameters between 18-month-old C57BL/6 mice treated with 50-70 mg/kg/day of losartan over a 4 month-period and age- and gender-matched mice receiving placebo. Losartan treatment significantly improved several activity measurements during treatment period compared to placebo controlled group, including increased time on treadmill, traveling activity, standing activity, and decreased grid contacts (p-values < 0.05, 0.001, 0.01; and 0.04 respectively). Grip strength did not improve in treatment group relative to control group over time. Serum IL-6 level in the treated group was significantly lower than that in the control group at the end of treatment, (30.3±12.9 vs. 173.0±59.5 pg/ml, p< 0.04), and mRNA expression of antioxidant enzymes catalase (3.9±0.9 vs. 1.0±0.4) and glutathione peroxidase (4.7±1.1 vs. 1.0±0.4) was significantly higher, P-value: 0.02, and 0.03 respectively) in quadriceps muscle after 4 months of treatment in treated and control groups. These results support the hypothesis that chronic losartan treatment improves skeletal muscle related activity measures in older mice, and that it is associated with more favorable relevant biological profiles in the treatment group. Additional studies are needed to 1) further quantify this functional improvement, 2) further identify mechanisms that influence this improvement, and 3) provide additional rationale for translating these findings into older adults.

Evidence-based nutritional and pharmacological interventions targeting chronic low-grade inflammation in middle-age and older adults: A systematic review and meta-analysis

“…The biological basis of ARBs effect on chronic LGI involves the blockade of angiotensin II type 1 receptor leading to inhibition of NF-κB signaling (Kleiber et al, 2010). In animal experiments, sartans have been shown to reduce IL-6 levels (Lin et al, 2014), improve memory (Ongali et al, 2014) and motor performance (Villapol et al, 2012) and protect against muscle loss (Burks et al, 2011). Moreover, a recent meta-analysis of RCTs and observational studies reported that the use of ARBs can reduce incidence risks by 35% for cognitive impairment and by 20% for AD (Zhuang et al, 2016).…”

Cytokine Signaling in Skeletal Muscle Wasting

“…Along this line, losartan, an ang II type I receptor blocker, improved muscle activity and reduced inflammation in older mice [48].…”

Oral Drugs Related with Muscle Wasting and Sarcopenia. A Review

“…Burks et al [20] indicate that the blockade of the AT1 receptor has beneficial effects on skeletal muscle remodeling in response to injury and conferring protection against disuse atrophy in sarcopenia by modulating the transforming growth factor-β (a known inhibitor of skeletal muscle regenerator) and Akt-mTOR pathways. In a study with older mice, it is suggested that treatment with losartan improves measures of physical function, decreases the inflammatory cytokine IL-6 and increases protective and antioxidant enzymes [21] . The Johns Hopkins University is conducting a clinical trial to see whether losartan can prevent the decrease in strength associated with aging, which will provide the evidence needed to clarify the association between sarcopenia and ARBs [22] .…”