Myocyte enhancer factor 2C function in skeletal muscle is required for normal growth and glucose metabolism in mice

Abstract

BackgroundSkeletal muscle is the most abundant tissue in the body and is a major source of total energy expenditure in mammals. Skeletal muscle consists of fast and slow fiber types, which differ in their energy usage, contractile speed, and force generation. Although skeletal muscle plays a major role in whole body metabolism, the transcription factors controlling metabolic function in muscle remain incompletely understood. Members of the myocyte enhancer factor 2 (MEF2) family of transcription factors play crucial roles in skeletal muscle development and function. MEF2C is expressed in skeletal muscle during development and postnatally and is known to play roles in sarcomeric gene expression, fiber type control, and regulation of metabolic genes.MethodsWe generated mice lacking Mef2c exclusively in skeletal muscle using a conditional knockout approach and conducted a detailed phenotypic analysis.ResultsMice lacking Mef2c in skeletal muscle on an outbred background are viable and grow to adulthood, but they are significantly smaller in overall body size compared to control mice and have significantly fewer slow fibers. When exercised in a voluntary wheel running assay, Mef2c skeletal muscle knockout mice aberrantly accumulate glycogen in their muscle, suggesting an impairment in normal glucose homeostasis. Consistent with this notion, Mef2c skeletal muscle knockout mice exhibit accelerated blood glucose clearance compared to control mice.ConclusionsThese findings demonstrate that MEF2C function in skeletal muscle is important for metabolic homeostasis and control of overall body size.

Nfix Induces a Switch in Sox6 Transcriptional Activity to Regulate MyHC-I Expression in Fetal Muscle

“…As expected, in the absence of Sox6, we found a significant reduction of firefly luciferase activity in all the conditions with the only notable exception of the 408 WT construct (Figure 2B), suggesting that Sox6 is promoting MyHC-I expression in embryonic myocytes without direct binding to its canonical binding sites. In order to identify a possible indirect mechanism by which Sox6 enhances MyHC-I expression in embryonic muscle, we focused on the transcription factor Mef2C, a known positive regulator of the slow phenotype (Wu et al., 2000, Potthoff et al., 2007, Anderson et al., 2015). To verify the interaction between Mef2C and the MyHC-I promoter in embryonic myoblasts, we performed a ChIP assay, which showed direct binding of Mef2C on the proximal MyHC-I promoter (Figure S3B).…”

“…The phenotype of post-natal muscle fibers is strictly regulated by extrinsic signals such as muscle activity and hormones (Butler-Browne et al., 1982, Gambke et al., 1983, Russell et al., 1988). Additionally, different factors controlling adult muscle plasticity have been identified, including the Nfatc (Calabria et al., 2009) and Mef2 (Wu et al., 2000, Potthoff et al., 2007, Anderson et al., 2015) transcription factor families and PGC-1α (Li et al., 2002). On the contrary, the molecular mechanisms by which muscle fiber diversity is achieved during pre-natal development are still poorly understood.…”

“…We found that Sox6 directly binds to the promoter of Mef2C and activates its expression in primary myofibers. Mef2C is part of a transcription factor family that is constitutively expressed in muscle cells since early embryogenesis (Edmondson et al., 1994) and plays an important role in the specification and maintenance of type I fibers (Chin et al., 1998, Wu et al., 2000, Anderson et al., 2015). Importantly, conditional deletion of Mef2C in skeletal muscle leads to a drastic reduction in slow-twitch fibers (Potthoff et al., 2007).…”

MEF2C regulates outflow tract alignment and transcriptional control of Tdgf1

“…The Mef2c and Tdgf1 probes have been described elsewhere (Anderson et al, 2015;Ding et al, 1998). Lineage analysis using Mef2c-AHF-Cre;Rosa26R mice and analyses of apoptosis with anti-cleaved caspase 3 (1:200) and of proliferation with antiphospho-histone H3 (1:200) were performed as described previously (McCulley et al, 2008;Sinha et al, 2012).…”

Single-cell RNA sequencing deconvolutes thein vivoheterogeneity of human bone marrow-derived mesenchymal stem cells

“…3c). MEF2C (myocyte enhancer factor 2C) is known to be essential for skeletal muscle development as well as attenuating MSC-derived cartilage hypertrophy in response to hypoxic conditioning 49,50 . ITGA8 (integrin subunit alpha 8) is a gene that modulates integrin activity to induce cartilage formation and protect against arthritis, while β1-integrin signaling enhances regeneration of myocytes 51,52 .…”