A New Role for Sterol Regulatory Element Binding Protein 1 Transcription Factors in the Regulation of Muscle Mass and Muscle Cell Differentiation

Abstract

The role of the transcription factors sterol regulatory element binding protein 1a (SREBP-1a) and SREBP-1c in the regulation of cholesterol and fatty acid metabolism has been well studied; however, little is known about their specific function in muscle. In the present study, analysis of recent microarray data from muscle cells overexpressing SREBP1 suggested that they may play a role in the regulation of myogenesis. We then demonstrated that SREBP-1a and -1c inhibit myoblast-to-myotube differentiation and also induce in vivo and in vitro muscle atrophy. Furthermore, we have identified the transcriptional repressors BHLHB2 and BHLHB3 as mediators of these effects of SREBP-1a and -1c in muscle. Both repressors are SREBP-1 target genes, and they affect the expression of numerous genes involved in the myogenic program. Our findings identify a new role for SREBP-1 transcription factors in muscle, thus linking the control of muscle mass to metabolic pathways.

Mitochondria-Associated Endoplasmic Reticulum Membrane (MAM) Integrity Is Required for Insulin Signaling and Is Implicated in Hepatic Insulin Resistance

“…The constructs used for inducing tethering between mitochondria and ER (AKAP1-FKBP-YFP and CFP-FRB-ER) were a generous gift of Gyorgy Hajnoczky and were used as previously described (16,18). Recombinant adenoviral genome carrying cyclophilin D (Ad-CypD) was generated from a vector encoding rat cyclophilin D (CypD) (21) by homologous recombination in the VmAdcDNA3 plasmid and amplified in HEK293 cells (22).…”

Bone muscle crosstalk targets muscle regeneration pathway regulated by core circadian transcriptional repressors DEC1 and DEC2

“…32 Importantly, DEC1 is reciprocally regulated by SREBP1 which requires proteolytic activation by MBTPS1. 16 SREBP-1 is a required transcription factor for most enzymes and receptors mediating lipolysis and lipogenesis and mitochondrial biogenesis, as well as myogenesis. 33 The light/dark entrained mammalian circadian clock is known to control glucose and lipid metabolism and mitochondrial oxidative metabolism.…”

“…[16][17][18] By analogy with the age-related onset of the Dmp1-Cre Mbtps1 cKO phenotype, DEC2 null mice show no deficit with respect to repair of embryonic muscle, however, as predicted for a repressor of myogenesis, regeneration after injury in post-natal DEC2( À / À ) mice is increased. 18 As SOL in Dmp1-Cre Mbtps1 cKO mice display characteristics of regenerating muscle, we hypothesized that a cycling circadian expression pattern for myogenic repressors DEC1/DEC2 could stimulate or reduce expression of pro-or anti-myogenic genes, respectively, during their 'down cycle'.…”

“…18 As SOL in Dmp1-Cre Mbtps1 cKO mice display characteristics of regenerating muscle, we hypothesized that a cycling circadian expression pattern for myogenic repressors DEC1/DEC2 could stimulate or reduce expression of pro-or anti-myogenic genes, respectively, during their 'down cycle'. Since Lecomte and colleagues have already identified ( þ ) and ( À ) transcriptional muscle-specific targets of DEC1/DEC2, 16 we asked whether expression of these target genes is temporally correlated with that of transcriptional regulators DEC1/DEC2 in Dmp1-Cre Mbtps1 cKO muscle? Importantly, the majority of muscle-specific target genes (79 out of 110) displayed the expected responses 16 as when DEC1/DEC2 are downregulated.…”

“…Since Lecomte and colleagues have already identified ( þ ) and ( À ) transcriptional muscle-specific targets of DEC1/DEC2, 16 we asked whether expression of these target genes is temporally correlated with that of transcriptional regulators DEC1/DEC2 in Dmp1-Cre Mbtps1 cKO muscle? Importantly, the majority of muscle-specific target genes (79 out of 110) displayed the expected responses 16 as when DEC1/DEC2 are downregulated. 2 As expression of both DEC1 and DEC2 is low in Dmp1-Cre Mbtps1 cKO SOL (array data deposited at NCBI, #GSE69985), this is the expected outcome.…”