Aldosterone Inhibits In Vitro Myogenesis by Increasing Intracellular Oxidative Stress via Mineralocorticoid Receptor

Abstract

Background: Despite clinical evidence indicating poor muscle health in subjects with primary aldosteronism (PA), it is still unclear whether the role of aldosterone in muscle metabolism is direct or mediated indirectly via factors, such as electrolyte imbalance or impaired glucose uptake. As one approach to clarify this issue, we investigated the effect of aldosterone on in vitro myogenesis and the potential mechanism explaining it.Methods: Myogenesis was induced in mouse C2C12 myoblasts with 2% horse serum. Immunofluorescence, quantitative reversetranscription polymerase chain reaction, Western blot, viability, and migration analyses were performed for experimental research.Results: Recombinant aldosterone treatment suppressed muscle differentiation from mouse C2C12 myoblasts in a dose-dependent manner, and consistently reduced the expression of myogenic differentiation markers. Furthermore, aldosterone significantly increased intracellular reactive oxygen species (ROS) levels in myotubes, and treatment with N-acetyl cysteine, a potent biological thiol antioxidant, reversed the decrease of myotube area, myotube area per myotube, nucleus number per myotube, and fusion index due to aldosterone through decreasing oxidative stress. A binding enzyme-linked immunosorbent assay confirmed that mineralocorticoid receptor (MR) interacted with aldosterone in C2C12 myoblasts, while eplerenone, an MR inhibitor, blocked aldosterone-stimulated intracellular ROS generation during myogenesis and markedly attenuated the suppression of in vitro myogenesis by aldosterone.Conclusion: These findings support the hypothesis that hypersecretion of aldosterone, like PA, directly contributes to muscular deterioration and suggest that antioxidants and/or MR antagonists could be effective therapeutic options to reduce the risk of sarcopenia in these patients.

Role of glucocorticoid and mineralocorticoid receptors in rainbow trout (Oncorhynchus mykiss) skeletal muscle: A transcriptomic perspective of cortisol action

“…The relationship between the mineralocorticoid receptor and cell cycle regulation has recently been addressed in a murine myotubes. It has been determined that aldosterone inhibited the process of muscle cell differentiation through increased intracellular oxidative stress, a phenomenon that was blocked in the presence of eplerenone (Lee et al, 2021), suggesting a fundamental role of MR in the modulation of muscle cell proliferation and differentiation.…”

The Role of Aldosterone in OSA and OSA-Related Hypertension

“…Lower skeletal muscle mass was found in female patients with PA than those with non-functional adrenal incidentaloma ( 55 ). It was also found that aldosterone impeded myogenesis in vitro and in vivo ( 56 , 57 ). Both undifferentiated myoblasts and differentiated myotubes express aldosterone receptors ( 58 ).…”

Mineralocorticoid Receptor Antagonists in Diabetic Kidney Disease

“…In addition, cortical thickness of brain has been shown to be correlated negatively with the expression of MR in human ( Parker et al, 2020 ). Finally, MR has been shown to be involved in the development of sarcopenia ( Burton et al, 2011 ; Lee et al, 2021 ). These findings demonstrate potential usefulness of nonsteroidal MRAs for geriatric syndromes in patients with diabetes by their potent anti-inflammatory properties.…”