Study summary · research use only
Targeting ERRs to counteract age-related muscle atrophy associated with physical inactivity: a pilot study
Plain-language summary
Paraphrased from the published abstract below — not a verdict on whether anything works.
This human pilot study enrolled Twenty women undergoing hip arthroplasty for coxarthrosis, divided into an active group (n = 10) and an inactive group (n = 10) based on self-reported activity, examining estrogen-related receptors (ERRs) in myoblasts isolated from muscle biopsies. Active subjects showed less functional limitation, higher handgrip strength, lower pain scores, and larger muscle fiber diameter, while inactive women's muscle showed higher NOX4 and lower SIRT1, PGC-1α, ERRα, and FNDC5. In myoblasts from inactive women, the ERR agonist SLU-PP-332 was associated with lower NOX4 and higher SIRT1, PGC-1α, ERRα, FNDC5, Akt, and Bcl-2, along with lower cytotoxicity, oxidative stress, and senescence markers, higher glutathione, and more myotube formation over 15 days of differentiation.
Abstract
Estrogen-related receptors has been suggested as a potential therapeutic target to counteract muscle decline associated with aging or inactivity, being known to regulate mitochondrial function and cellular respiration by up-regulating key factors in muscle responses to exercise. This study aimed to evaluate the targeting of ERRs in myoblasts isolated from the skeletal muscle of inactive women by assessing the metabolic and expression changes associated with its activation. Twenty women undergoing hip arthroplasty for coxarthrosis were enrolled and divided into an active group (n = 10) and an inactive group (n = 10) based on self-reported physical activity. During surgery, muscle biopsies were taken for histological and western blotting analysis, measuring the expression levels of NADPH oxidase 4 (NOX4), sirtuin 1 (SIRT1), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), estrogen related receptor alpha (ERRα), and fibronectin type III domain-containing protein 5 (FNDC5). Primary cultures of myoblasts were set up from the muscle tissue of inactive women and treated with the ERRs agonist, SLU-PP-332, for subsequent qualitative and quantitative investigations. In addition, myoblasts were differentiated into myotubes for 15 days, and the success of differentiation was evaluated by immunofluorescence analysis. Clinical and instrumental evaluation showed less functional limitation, higher handgrip strength values, and significantly reduced visual analogue scale scores in active subjects, in association with a significant increase in muscle fiber diameter. In addition, significantly higher expression of NOX4, concomitant with reduced levels of SIRT1, PGC-1α, ERRα, and FNDC5, was detected in the muscle tissue of inactive women. Interestingly, SLU-PP-332 treatment promoted down-regulation of NOX4 and upregulation of SIRT1, PGC-1α, ERRα, FNDC5, Akt, and B-cell lymphoma 2 (Bcl-2) in myoblasts, reducing cytotoxicity, oxidative stress, and senescence, as well as increasing levels of reduced glutathione. Furthermore, SLU-PP-332 treatment promoted abundant myotube formation, positively influencing cell differentiation. Targeting ERRs could represent a promising therapeutic strategy to counteract muscle atrophy in elderly and sedentary subjects. However, further studies are needed to clarify the molecular mechanisms involved and explore the impact of ERRs activation on muscle metabolism.
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