FHL3 promotes the formation of fast glycolytic muscle fibers by interacting with YY1 and muscle glycolytic metabolism

Abstract

The proportions of the various muscle ber types are important in the regulation of skeletal muscle metabolism, as well as animal meat production. Four-and-a-half LIM domain protein 3 (FHL3) is highly expressed in fast glycolytic muscle bers and differentially regulates the expression of myosin heavy chain (MyHC) isoforms at the cellular level. Whether FHL3 regulates the transformation of muscle ber types in vivo and the regulatory mechanism are unclear. In this study, muscle-speci c FHL3 transgenic mice were generated by random integration, and lentivirus-mediated gene knockdown or overexpression in muscles of mice or pigs was conducted. Functional analysis showed that overexpression of FHL3 in muscles signi cantly increased the proportion of fast-twitch myo bers and muscle mass but decreased muscle succinate dehydrogenase (SDH) activity and whole-body oxygen consumption. Lentivirusmediated FHL3 knockdown in muscles signi cantly decreased muscle mass and the proportion of fasttwitch myo bers. Mechanistically, FHL3 directly interacted with the Yin yang 1(YY1) DNA-binding domain, repressed the binding of YY1 to the fast glycolytic MyHC2b gene 5' regulatory region, and thereby decreased MyHC2b expression. FHL3 also competed with EZH2 to bind the repression domain of YY1 and reduced H3K27me3 enrichment in the MyHC2b regulatory region. Moreover, FHL3 overexpression reduced glucose tolerance by affecting muscle glycolytic metabolism, and its mRNA expression in muscle was positively associated with hemoglobin A1c (HbA1c) in patients with type 2 diabetes. Therefore, FHL3 is a novel potential target gene for the treatment of muscle metabolism-related diseases and improvement of animal meat production.

“Biqi” Bayberry Extract Promotes Skeletal Muscle Fiber Type Remodeling by Increasing Fast Myofiber Formation via the Akt/FoxO1 Pathway in Mice

“…Moreover, consistent with these findings, the oxygen consumption was markedly decreased and RER was greatly increased, indicating a high glycolytic metabolism level in BBE-group mice. Consistent with our findings, previous studies showed that inducing fast-twitch myofibers switching by transgenic models or lentivirus treatment significantly improved the muscle performance with an increase in whole-limb grip strength and regulated the glycolytic metabolism with a decrease in O 2 consumption and an increase in RER [5,22]. The above results demonstrated that BBE could increase fast-twitch myofibers proportion and promote myofibers type reprogramming.…”

“…These results suggest bayberry extract shows great potential in regulating glucose metabolism and homeostasis. Taken from the growing body of evidence indicating a strong correlation between fast-twitch myofiber and the regulation of glucose metabolism and homeostasis together [ 13 , 22 , 23 ], bayberry is likely to have influence on the fast-twitch myofiber. Nevertheless, the impact of bayberry extract on the composition of skeletal myofibers is rarely reported.…”

Orientin Promotes Antioxidant Capacity, Mitochondrial Biogenesis, and Fiber Transformation in Skeletal Muscles through the AMPK Pathway

“…In contrast, oxidative muscle fibers, comprising types I and IIa, display elevated levels of oxidative metabolic enzymes accompanied by increased mitochondrial activity. Glycolytic muscle fibers, particularly type IIb, demonstrate a reduced abundance of mitochondria and heightened activity of the glycolytic enzyme LDH. , Muscle fibers can undergo interconversion in response to physiological and nutritional factors. Patients with OSA exhibit abnormal genioglossus structure and function, characterized by higher than normal proportions of type II fibers and decreased fatigue resistance …”

Transcriptome profiling of fast/glycolytic and slow/oxidative muscle fibers in aging and obesity

“…In the case of obesity, evidence indicates that obese individuals had increased fast-twitch fibers [ 14 ]. However, the distribution of different fiber types exhibits spatial specificity, but most studies analyze local areas rather than the entire cross-section of fibers [ 15 – 18 ]. Currently, it remains unclear whether the changes in fiber types are consistent under different physiological and pathological conditions, and the trend of these changes is also unclear.…”