Inhibition of myostatin in mice improves insulin sensitivity via irisin-mediated cross talk between muscle and adipose tissues

Abstract

Background/ObjectiveIn mice, a high fat diet (HFD) induces obesity, insulin resistance and myostatin production. We tested whether inhibition of myostatin in mice can reverse these HFD-induced abnormalities.Subjects/MethodsC57BL/6 mice were fed a HFD for 16 weeks including the final 4 weeks some mice were treated with an anti-myostatin peptibody. Body composition, the respiratory exchange ratio plus glucose and insulin tolerance tests were examined. Myostatin knock down in C2C12 cells was performed using ShRNA lentivirus. Adipose tissue-derived stem cells were cultured to measure their reponses to conditioned media from C2C12 cells lacking myostatin, or to recombinant myostatin or Irisin. Isolated peritoneal macrophages were treated with myostatin or Irisin to determine if myostatin or Irisin induce inflammatory mechanisms.ResultsIn HFD-fed mice, peptibody treatment stimulated muscle growth and improved insulin resistance. The improved glucose and insulin tolerances were confirmed when we found increased muscle expression of p-Akt and the glucose transporter, Glut4. In mice fed the HFD, the peptibody suppressed macrophage infiltration and the expression of proinflammatory cytokines in both muscle and adipocytes. Inhibition of myostatin caused the conversion of white (WAT) to brown adipose tissue (BAT) while stimulating fatty acid oxidation and increasing energy expenditure. The related mechanism is a muscle-to-fat cross talk mediated by Irisin. Myostatin inhibition increased PGC-1α expression and Irisin production in muscle. Irisin then stimulated WAT browning. Irisin also suppresses inflammation and stimulates macrophage polarization from M1 to M2 types.Concusionthese results uncover a metabolic pathway from an increase in myostatin that suppresses Irisin leading to activation of inflammatory cytokines and insulin resistance. Thus, myostatin is a potential therapeutic target to treat insulin resistance of type II diabetes as well as the shortage of brown/beige fat in obesity.

Biochemistry and Biology of GDF11 and Myostatin

“…A systemic signal, possibly initiated by a reduction in body size or a change in a specific tissue, is quite plausible. For example, there is clear evidence for cross talk between adipose tissue and cardiac 160, 161 and skeletal 133, 162, 163 tissues. Thus, any interpretation of a direct effect of rGDF11 on the myocardium must be considered in the context of its systemic effects.…”

Exercise regulation of adipose tissue

“…These data suggest a unique role for myostatin as a muscle myokine that inhibits the beiging of scWAT. 51,57 Meteorin-like (Metrnl) Metrnl was identified from primary myotubes overexpressing PGC1a4 40 , the PGC1a splice isoform that had been shown to regulates muscle hypertrophy and energy expenditure. 58 Increasing circulating Metrnl by 5-6-fold in mice by injection of adenoviral vectors increased whole-body energy expenditure, an effect associated with an increase in beiging of scWAT.…”

Modulation of transforming growth factor-β/follistatin signaling and white adipose browning: therapeutic implications for obesity related disorders

“…They also demonstrated significant induction of adipocyte-specific marker adiponectin and energy-sensing AMP-activated protein kinase (AMPK) in differentiating MEF primary cultures isolated from Mst-KO mice compared to the WT mice. Subsequent studies published from several laboratories have confirmed that Mst inhibition promotes white adipose browning and improves insulin sensitivity [74], [75], [76]. Shan et al [77] further confirmed that loss of Mst results in numerous small-sized brown adipocyte-like cells filled with multilocular small lipid droplets, representing key features of WAT browning and upregulation of a beige-specific gene signature.…”

“…In the same study, irisin, a protein product of the Fndc5 gene, was identified as a key mediator of WAT browning via activation of the AMPK-PGC1α-Fndc5 pathway. The absence of Mst has also been shown to improve insulin sensitivity in several in vitro and in vivo models [74], [76], Using an anti-Mst peptibody in C57BL/6 mice, Dong et al [74] reported an increased expression of irisin in skeletal muscle, which contributed to WAT browning. Loss-of-function Mst mutation in Meishan pigs resulted in increased insulin sensitivity and browning of WAT [76].…”