The Ski proto-oncogene regulates body composition and suppresses lipogenesis

Abstract

Objective: The Ski gene regulates skeletal muscle differentiation in vitro and and in vivo. In the c-Ski overexpression mouse model there occurs marked skeletal muscle hypertrophy with decreased adipose tissue mass. In this study, we have investigated the underlying molecular mechanisms responsible for the increased skeletal muscle and decreased adipose tissue mass in the c-Ski mouse. Approach: Growth and body composition analysis (tissue weights and dual energy X-ray absorptiometry) coupled with skeletal muscle and white adipose gene expression and metabolic phenotyping in c-Ski mice and wild-type (WT) littermate controls was performed. Results: The growth and body composition studies confirmed the early onset of accelerated body growth, with increased lean mass and decreased fat mass in the c-Ski mice. Gene expression analysis in skeletal muscle from c-Ski mice compared with WT mice showed significant differences in myogenic and lipogenic gene expressions that are consistent with the body composition phenotype. Skeletal muscle of c-Ski mice had significantly repressed Smad1, 4, 7 and myostatin gene expression and elevated myogenin, myocyte enhancer factor 2, insulin-like growth factor-1 receptor and insulin-like growth factor-2 expression. Strikingly, expression of the mRNAs encoding the master lipogenic regulators, sterol-regulatory enhancer binding protein 1c (SREBP1c), and the nuclear receptor liver X-receptor-a, and their downstream target genes, SCD-1 and FAS, were suppressed in skeletal muscle of c-Ski mice, as were the expressions of other nuclear receptors involved in adipogenesis and metabolism, such as peroxisome proliferator-activated receptor-g, glucocorticoid receptor and retinoic acid receptor-related orphan receptor-a. Transfection analysis demonstrated Ski repressed the SREBP1c promoter. Moreover, palmitate oxidation and oxidative enzyme activity was increased in skeletal muscle of c-Ski mice. These results suggest that the Ski phenotype involves attenuated lipogenesis, decreased myostatin signalling, coupled to increased myogenesis and fatty acid oxidation. Conclusion: Ski regulates several genetic programs and signalling pathways that regulate skeletal muscle and adipose mass to influence body composition development, suggesting that Ski may have a role in risk for obesity and metabolic disease.

Peroxisome Proliferator-activated Receptor γ (PPARγ) Mediates a Ski Oncogene-induced Shift from Glycolysis to Oxidative Energy Metabolism

“…A more recent analysis of the affected muscles in those mice demonstrated a decreased expression of several genes involved in lipid synthesis, indicating that Ski suppresses lipogenesis, consistent with our findings in Ski-CEFs (17). Those studies also agree with our results by showing that increased expression of Ski enhanced the capacity of skeletal muscle to oxidize fatty acids.…”

“…Ski knockout mice display a dramatic reduction of skeletal muscle development (15), as well as the virtual absence of brown adipose tissue (16). Transgenic mice overexpressing c-Ski exhibit a remarkable increase of skeletal muscle mass but a decrease of adipose tissue (17). In these mice, selective hypertrophy of type IIb fast skeletal muscle fibers is accompanied by increased lipid oxidation despite decreased expression of the transcription factor peroxisome proliferator-activated receptor ␥ (PPAR␥), a key regulator of lipogenesis (17).…”

“…Transgenic mice overexpressing c-Ski exhibit a remarkable increase of skeletal muscle mass but a decrease of adipose tissue (17). In these mice, selective hypertrophy of type IIb fast skeletal muscle fibers is accompanied by increased lipid oxidation despite decreased expression of the transcription factor peroxisome proliferator-activated receptor ␥ (PPAR␥), a key regulator of lipogenesis (17). These findings suggest that Ski plays a role in regulating lipid metabolism, perhaps mediated by an effect on the expression or transcriptional activity of PPAR␥.…”

Metabolic Functions of Myostatin and GDF11

“…Transgenic mice expressing c-Ski under control of the murine sarcoma virus long terminal repeat have increased lean mass and reduced body fat [79, 80]. Similarly, skeletal muscle-specific IGF1 transgenic mice and pigs [81, 82] and skeletal muscle-specific constitutively active Akt transgenic mice [83, 84] have reduced adipose tissue mass compared to non-transgenic controls.…”

SnoN as a novel negative regulator of TGF-β/Smad signaling: a target for tailoring organ fibrosis

“…These models suggest that having two functional copies of SnoN and Ski is critical in regulating key genetic events during embryonic patterning and development. This may be important as dysregulation of these proteins has been linked to several disease states within adult tissues (7,9,31,37,54,66,67). SnoN has been detected within all adult tissues tested, albeit typically at low, basal levels.…”