Increased Smad signaling and reduced MRF expression in skeletal muscle from obese subjects
Rani Watts1, Andrew J McAinch, John B Dixon
1School of Exercise and Nutrition Sciences, Deakin University, Melbourne, Australia.
Objective:
The molecular mechanisms underpinning the loss of skeletal muscle mass and strength associated with insulin resistance remain to be extensively investigated. There is mounting recognition that certain ligands of the transforming growth factor (TGF)-β family are upregulated in insulin resistant states, including obesity. This study analyses the expression of potent ligands of this family, TGF-β1 and myostatin (MSTN) and downstream components of the canonical TGF-β family signaling pathway (Smads) in skeletal muscle from lean and insulin resistant obese subjects.
Design And Methods:
Biopsies taken from the rectus abdominis muscle of lean (n = 13) and obese subjects (n = 20) were analyzed for the expression of TGF-β1 and MSTN as well as TGF-β signaling components, Smad2, 3, and 4, and transcription of the muscle regulatory factors (MRFs), MyoD and myogenin.
Results:
Increases in Smad2 and Smad3 phosphorylation, Smad4 and total Smad3 were observed to be coincident with altered transcription of MyoD and myogenin. TGF-β1 and MSTN protein levels were not significantly altered.
Conclusion:
Thus, increased Smad signaling is likely to account for, at least, a proportion of obesity and insulin resistance-related muscle atrophy through reduced MRF, particularly MyoD, transcription. The major regulatory ligand may not be MSTN and further members of the TGF-β1 superfamily should be considered.
Insights
Insulin resistance and obesity may cause muscle atrophy via increased Smad signaling, which reduces muscle regulatory factor (MRF) transcription. Transforming growth factor (TGF)-β1 and myostatin (MSTN) protein levels were unchanged.
Area of Science:
- Muscle physiology and molecular biology.
- Endocrinology and metabolic disorders.
Background:
- Insulin resistance, often associated with obesity, leads to skeletal muscle mass and strength loss.
- Transforming growth factor (TGF)-β family ligands, including TGF-β1 and myostatin (MSTN), are implicated in insulin resistance.
- The role of canonical TGF-β signaling pathway components (Smads) in obesity-related muscle atrophy requires further investigation.
Purpose of the Study:
- To investigate the expression of TGF-β1, MSTN, and Smad signaling pathway components in skeletal muscle of lean versus obese, insulin-resistant individuals.
- To analyze the relationship between TGF-β signaling and the transcription of muscle regulatory factors (MRFs) in the context of obesity and insulin resistance.
Main Methods:
- Skeletal muscle biopsies were obtained from lean (n=13) and obese (n=20) subjects.
- Expression analysis included TGF-β1, MSTN, Smad2, Smad3, Smad4, and MRFs (MyoD, myogenin) via Western blotting and RT-PCR.
Main Results:
- Increased phosphorylation of Smad2 and Smad3, along with elevated levels of Smad4 and total Smad3, were observed in obese subjects.
- Altered transcription of MyoD and myogenin was coincident with the changes in Smad signaling.
- TGF-β1 and MSTN protein levels did not show significant alterations between the groups.
Conclusions:
- Increased Smad signaling in skeletal muscle likely contributes to obesity and insulin resistance-related muscle atrophy by reducing MRF transcription, particularly MyoD.
- Myostatin (MSTN) may not be the primary regulatory ligand involved; other members of the TGF-β1 superfamily warrant further investigation.
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