Skeletal muscle inflammation and atrophy are closely associated with metabolic impairment such as insulin resistance. Quercetin, a natural polyphenol flavonoid, is known to elicit anti-inflammatory and antioxidant activities. In this study, we investigated its effect on obesity-induced skeletal muscle inflammation and atrophy in mice. Male C57BL/6 mice were fed a regular diet, a high-fat diet (HFD), and an HFD supplemented with quercetin for nine weeks. Quercetin reduced levels of inflammatory cytokines and macrophage accumulation in the skeletal muscle of the HFD-fed obese mice. It also reduced transcript and protein levels of the specific atrophic factors, Atrogin-1 and MuRF1, in the skeletal muscle of the HFD-fed obese mice, and protected against the reduction of muscle mass and muscle fiber size. In vitro, quercetin markedly diminished transcript levels of inflammatory receptors and activation of their signaling molecules (ERK, p38 MAPK, and NF-κB) in cocultured myotubes/macrophages, and this was accompanied by reduced expression of the atrophic factors. Together, these findings suggest that quercetin reduces obesity-induced skeletal muscle atrophy by inhibiting inflammatory receptors and their signaling pathway. Quercetin may be useful for preventing obesity-induced muscle inflammation and sarcopenia.

In this study, we investigated effects of pine nut oil (PNO) on high-fat-diet (HFD)-induced obesity and metabolic dysfunction in skeletal muscle and brown adipose tissue (BAT). Male C57BL/6 mice were fed a HFD with 15% energy from lard and 30% energy from either soybean oil (SBO-HFD) or PNO (PNO-HFD) for 12 weeks. The PNO-HFD resulted in less weight gain and intramuscular lipid accumulation than the SBO-HFD and was accompanied by upregulation of transcripts and proteins related to oxidative metabolism and phosphorylation of AMP-activated protein kinase (AMPK), as well as molecules selectively expressed in type I and type IIa muscle fibers. In addition, uncoupling protein-1 was upregulated in BAT. These beneficial metabolic effects were partly associated with the dual ligand activity of pinolenic acid, which is abundant in PNO, for peroxisome proliferator-activated receptors α and δ. Our findings suggest that PNO may have potential as a dietary supplement for counteracting obesity and metabolic dysregulation.

Obesity-induced skeletal muscle inflammation is characterized by increased macrophage infiltration and inflammatory cytokine production. In this study, we investigated whether 4-1BB, a member of the TNF receptor superfamily (TNFRSF9) that provides inflammatory signals, participates in obesity-induced skeletal muscle inflammation. Expression of the 4-1BB gene, accompanied by increased levels of inflammatory cytokines, was markedly upregulated in the skeletal muscle of obese mice fed a high-fat diet, in muscle cells treated with obesity factors, and in cocultured muscle cells/macrophages. In vitro stimulation of 4-1BB with agonistic antibody increased inflammatory cytokine levels in TNFα-pretreated muscle cells, and this effect was absent in cells derived from 4-1BB-deficient mice. Conversely, disruption of the interaction between 4-1BB and its ligand (4-1BBL) with blocking antibody decreased the release of inflammatory cytokines from cocultured muscle cells/macrophages. Moreover, deficiency of 4-1BB markedly reduced macrophage infiltration and inflammatory cytokine production in the skeletal muscle of mice fed a high-fat diet. These findings indicate that 4-1BB mediates the inflammatory responses in obese skeletal muscle by interacting with its ligand 4-1BBL on macrophages. Therefore, 4-1BB and 4-1BBL may be useful targets for prevention of obesity-induced inflammation in skeletal muscle.

Obesity-induced inflammation causes skeletal muscle atrophy accompanied by disruption of oxidative metabolism and is implicated in metabolic complications such as insulin resistance and type 2 diabetes. We previously reported that 4-1BB, a member of the tumor necrosis factor receptor superfamily, participated in obesity-induced skeletal muscle inflammation. Here, we show that the absence of 4-1BB in obese mice fed a high-fat diet led to a decrease in expression of atrophic factors (MuRF1 and Atrogin-1) with suppression of NF-κB activity, and that this was accompanied by increases in mitochondrial oxidative metabolic genes/proteins (e.g., PGC-1α, CPT1β, etc.) expression and oxidative muscle fibers marker genes/proteins in the skeletal muscle. These findings suggest that 4-1BB-mediated inflammatory signaling could be a potential target for combating obesity-related muscle atrophy and metabolic derangement in skeletal muscle.