Morroniside ameliorates inflammatory skeletal muscle atrophy via inhibiting canonical and non-canonical NF-κB and regulating protein synthesis/degradation

Abstract

No drug options exist for skeletal muscle atrophy in clinical, which poses a huge socio-economic burden, making development on drug interventions a general wellbeing need. Patients with a variety of pathologic conditions associated with skeletal muscle atrophy have systemically elevated inflammatory factors. Morroniside, derived from medicinal herb Cornus officinalis, possesses anti-inflammatory effect. However, whether and how morroniside combat muscle atrophy remain unknown. Here, we identified crucial genetic associations between TNFα/NF-κB pathway and grip strength based on population using 377,807 European participants from the United Kingdom Biobank dataset. Denervation increased TNFα in atrophying skeletal muscles, which inhibited myotube formation in vitro. Notably, morroniside treatment rescued TNFα-induced myotube atrophy in vitro and impeded skeletal muscle atrophy in vivo, resulting in increased body/muscles weights, No. of satellite cells, size of type IIA, IIX and IIB myofibers, and percentage of type IIA myofibers in denervated mice. Mechanistically, in vitro and/or in vivo studies demonstrated that morroniside could not only inhibit canonical and non-canonical NF-κB, inflammatory mediators (IL6, IL-1b, CRP, NIRP3, PTGS2, TNFα), but also down-regulate protein degradation signals (Follistatin, Myostatin, ALK4/5/7, Smad7/3), ubiquitin-proteasome molecules (FoxO3, Atrogin-1, MuRF1), autophagy-lysosomal molecules (Bnip3, LC3A, and LC3B), while promoting protein synthesis signals (IGF-1/IGF-1R/IRS-1/PI3K/Akt, and BMP14/BMPR2/ALK2/3/Smad5/9). Moreover, morroniside had no obvious liver and kidney toxicity. This human genetic, cells and mice pathological evidence indicates that morroniside is an efficacious and safe inflammatory muscle atrophy treatment and suggests its translational potential on muscle wasting.

Morroniside Inhibits Inflammatory Bone Loss through the TRAF6-Mediated NF-κB/MAPK Signalling Pathway

“…Morroniside is an iridoid glycoside and has attracted increasing attention in recent years in terms of its medicinal value. Studies have shown that morroniside can regulate protein expression to improve inflammatory skeletal muscle atrophy [30] and can reduce cartilage destruction by reducing the expression of inflammatory mediators (such as Cox-2, Mmp3, and Mmp13) in articular cartilage [28]. More importantly, it can promote the differentiation of osteoblasts, inhibit the differentiation of osteoclasts, and enhance bone mineral density, to play an anti-osteoporosis role [25], which also provides a certain basis for our study on the anti-inflammatory bone loss of mice using morroniside.…”

Plant-Derived Senotherapeutics for the Prevention and Treatment of Intervertebral Disc Degeneration and Aging

“…Morroniside is an iridoid glycoside ( Figure 1 ) and the main active ingredient isolated from Cornus officinalis of the dogwood family Cornaceae [ 183 ]. Morroniside has been shown to exert many biological effects, such as anti-inflammatory, anti-apoptotic, anti-oxidant, cardioprotective and neuroprotective via several mechanisms and signaling pathways, i.e., STAT3, NF-κB, MAPK and PI3K/Akt pathways and molecules regulating the autophagic flux [ 184 , 185 , 186 , 187 , 188 , 189 ]. It has thus long been used to treat degenerative diseases of the nervous system, to inhibit platelet aggregation, to prevent diabetic angiopathies and renal damage, to treat OA and to reduce bone resorption [ 190 ].…”

Phytochemicals against Osteoarthritis by Inhibiting Apoptosis

“…Morroniside [Cornaceae; Cornus officinalis Siebold and Zucc] (MR), derived from the botanical drug Cornus officinalis, is an iridoid glycoside with many biological effects, such as anti-inflammatory, antioxidant, and anti-apoptotic activities [112]. MR can be used to treat OA by acting through the anti-apoptosis function.…”