Yap regulates skeletal muscle fatty acid oxidation and adiposity in metabolic disease

Abstract

Obesity is a major risk factor underlying the development of metabolic disease and a growing public health concern globally. Strategies to promote skeletal muscle metabolism can be effective to limit the progression of metabolic disease. Here, we demonstrate that the levels of the Hippo pathway transcriptional co-activator YAP are decreased in muscle biopsies from obese, insulin-resistant humans and mice. Targeted disruption of Yap in adult skeletal muscle resulted in incomplete oxidation of fatty acids and lipotoxicity. Integrated ‘omics analysis from isolated adult muscle nuclei revealed that Yap regulates a transcriptional profile associated with metabolic substrate utilisation. In line with these findings, increasing Yap abundance in the striated muscle of obese (db/db) mice enhanced energy expenditure and attenuated adiposity. Our results demonstrate a vital role for Yap as a mediator of skeletal muscle metabolism. Strategies to enhance Yap activity in skeletal muscle warrant consideration as part of comprehensive approaches to treat metabolic disease.

Multifactorial Mechanism of Sarcopenia and Sarcopenic Obesity. Role of Physical Exercise, Microbiota and Myokines

“…The infiltration of the adipose tissue by the pro-inflammatory immune cells such as classically activated (M1) macrophages, CD8+ and Th1 T cells and the reduced number of Treg cells further increase the production of inflammatory mediators [ 166 ]. Yap levels in the skeletal muscles of obese and insulin-resistant humans and animals were significantly lowered [ 167 ].…”

“…Furthermore, it has been associated with inflammation and could damage muscle function and quality [ 26 , 199 , 201 ]. It was recently shown that inhibition of Yap impairs fatty acid oxidation and leads to lipotoxicity in skeletal muscle [ 167 ]. Type I fibers (slow-twitch oxidation fibers) collect more lipids with age in humans than type II fibers [ 202 ].…”

Hydroxysafflor Yellow A Alters Fuel Selection From Glucose to Fat by Activating the PPARδ Pathway in Myocytes

“…We then checked the effect of HSYA on lipogenesis and lipid oxidation, which showed that HSYA might elevate lipid utilization. Low-intensity exercise has been reported to induce a fuel selection switch from glucose to lipid, and intriguingly, this metabolic fuel strategy was enhanced in mice by HSYA treatment . As we all know, branched-chain amino acid utilization is also involved in fuel use during exercise, and a previous study showed that efficient branched-chain amino acid utilization contributes to high intrinsic exercise capacity and endurance capacity .…”

“…Low-intensity exercise has been reported to induce a fuel selection switch from glucose to lipid, and intriguingly, this metabolic fuel strategy was enhanced in mice by HSYA treatment. 43 As we all know, branched-chain amino acid utilization is also involved in fuel use during exercise, and a previous study showed that efficient branched-chain amino acid utilization contributes to high intrinsic exercise capacity and endurance capacity. 7 However, in this paper, we only studied the effect of HSYA on glucose utilization and fat utilization in skeletal muscle.…”

The Neuromuscular Junction: Roles in Aging and Neuromuscular Disease

“…The highly conserved Hippo pathway regulates several cellular processes. The main effectors of this pathway, Yap (Yes-Associated Protein) and Taz (Transcriptional co-activator with PDZ binding motif) are activated by exercise and interact with various signaling pathways to increase skeletal muscle size [ 161 , 162 , 163 , 164 , 165 ]. Muscles lacking Yap result in decreased muscle strength due to poor neuromuscular transmission, consistent with reduced AChR density and impaired clustering, reduced endplate occupancy, and reduced miniature endplate potential frequency [ 166 ].…”