Angiotensin-II-induced Muscle Wasting is Mediated by 25-Hydroxycholesterol via GSK3β Signaling Pathway

Abstract

While angiotensin II (ang II) has been implicated in the pathogenesis of cardiac cachexia (CC), the molecules that mediate ang II's wasting effect have not been identified. It is known TNF-α level is increased in patients with CC, and TNF-α release is triggered by ang II. We therefore hypothesized that ang II induced muscle wasting is mediated by TNF-α. Ang II infusion led to skeletal muscle wasting in wild type (WT) but not in TNF alpha type 1 receptor knockout (TNFR1KO) mice, suggesting that ang II induced muscle loss is mediated by TNF-α through its type 1 receptor. Microarray analysis identified cholesterol 25-hydroxylase (Ch25h) as the down stream target of TNF-α. Intraperitoneal injection of 25-hydroxycholesterol (25-OHC), the product of Ch25h, resulted in muscle loss in C57BL/6 mice, accompanied by increased expression of atrogin-1, MuRF1 and suppression of IGF-1/Akt signaling pathway. The identification of 25-OHC as an inducer of muscle wasting has implications for the development of specific treatment strategies in preventing muscle loss.

Cardiac-Specific Overexpression of Catalytically Inactive Corin Reduces Edema, Contractile Dysfunction, and Death in Mice with Dilated Cardiomyopathy

“…Cardiac-specific overexpression of corin-Tg(i) upregulated pSer9-GSK3β/total GSK3β levels toward corin-WT/WT controls. Phosphorylated GSK3β myocardial levels are involved in regulation of protein synthesis pathways associated with cachexia [58,59] and cardiac Wnt signaling activation [50,60]. The upregulated pSer9-GSK3β/total GSK3β levels we observed may be the result of Wnt-corin interactions or it may be the result of the overall improvement in systolic function observed in these mice.…”

SARS-CoV-2/Renin–Angiotensin System: Deciphering the Clues for a Couple with Potentially Harmful Effects on Skeletal Muscle

“…In this context, IL-6 would act by enhancing UPS activation and E3-ligase expression (catabolic path), decreasing the levels of IRS-1 and phosphorylated Akt (anabolic path), and increasing the suppressor of cytokine signaling 3 expression (inflammatory path) [57]. Ang II can also activate the tumoral necrosis factor α (TNF-α) /TNF receptor 1 complex, which inactivates Akt, favoring glycogen synthase kinase 3 beta (GSK3β) activation, and, consequently, the activation of UPS and protein degradation [58]. Finally, Ang II/AT1R binding can activate transforming growth factor β (TGFβ) signaling, leading to an inflammatory state through extracellular signal-regulated kinase 1/2 and Jun N-terminal kinase pathway activation [59].…”

Transcriptomic profile of semitendinosus muscle of bulls of different breed and performance

“…The gsk3β overexpression restricts protein synthesis and expression of genes responsible for synthesis of muscle proteins, and thus hypertrophy of muscle fibers (Mohamed et al 2010 ). Moreover, it has been presented that activation of the GSK3β signal pathway leads to elevated expression of proteolysis markers, myogenesis disruption, and to muscle loss (Shen et al 2017 ). However, inhibition of GSK3β prevents muscle atrophy in mice (Shen et al 2017 ) and guinea pigs (Verhees et al 2013 ), and it further prevents development of myotonic dystrophy type 1 (DM1), eventually leading to skeletal muscle being characterized by higher fiber density, and normal fiber size (Wei et al 2018 ).…”

“…Moreover, it has been presented that activation of the GSK3β signal pathway leads to elevated expression of proteolysis markers, myogenesis disruption, and to muscle loss (Shen et al 2017 ). However, inhibition of GSK3β prevents muscle atrophy in mice (Shen et al 2017 ) and guinea pigs (Verhees et al 2013 ), and it further prevents development of myotonic dystrophy type 1 (DM1), eventually leading to skeletal muscle being characterized by higher fiber density, and normal fiber size (Wei et al 2018 ). Other researchers also observed that GSK3β is a negative regulator of skeletal muscle growth, and its insufficiency stimulates myogenic differentiation and myotube formation (van der Velden et al 2008 ; Ma et al 2014 ).…”