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Genetic disruption of Smad7 impairs skeletal muscle growth and regeneration
Tatiana V Cohen1,2, Helen D Kollias1, Naili Liu1
1Centre for Genetic Muscle Disorders, Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, MD, USA.
Key Points:
Smad7 is an intracellular antagonist of transforming growth factor-β signalling pathways and modulates muscle growth in vivo. Loss of Smad7 results in decreased muscle mass, reduced force generation, fibre type switching from glycolytic towards oxidative type and delayed recovery from injury. Upregulated Smad2/3 signalling in Smad7(-/-) muscle results in reduced myoblast proliferation and differentiation. Smad7 is an important regulator of muscle growth and may be a potential intracellular therapeutic target for muscle disorders.
Abstract:
The transforming growth factor-β (TGF-β) family of growth factors plays an essential role in mediating cellular growth and differentiation. Myostatin is a muscle-specific member of the TGF-β superfamily and a negative regulator of muscle growth. Myostatin inhibitors are currently being pursued as therapeutic options for muscle disorders. Smad7 inhibits intracellular myostatin signalling via Smad2/3, and thus presents a means of regulating myostatin and potentiating muscle growth. We investigated the functional loss of Smad7 on muscle in vivo by examining muscle growth and differentiation in mice deficient in Smad7 (Smad7(-/-) ). Smad7(-/-) mice showed reduced muscle mass, hypotrophy and hypoplasia of muscle fibres, as well as an increase in oxidative fibre types. Examination of muscle strength showed reduced force generation in vivo and ex vivo compared to wild-type controls. Analysis of muscle regeneration showed a delay in recovery, probably as a result of decreased activation, proliferation and differentiation of satellite cells, as confirmed in vitro. Additionally, myostatin expression was upregulated in Smad7(-/-) muscle. Our findings suggest that increased Smad2/3 signalling in the absence of Smad7 inhibition impedes muscle growth and regeneration. Taken together, our experiments demonstrate that Smad7 is an important mediator of muscle growth in vivo. Our studies enhance our understanding of in vivo TGF-β pathway modulation and suggest that Smad7 may be an important therapeutic target for muscle disorders.
Insights
Smad7 deficiency impairs muscle growth and regeneration by upregulating TGF-β signaling. Loss of Smad7 leads to reduced muscle mass and delayed recovery, highlighting Smad7 as a therapeutic target for muscle disorders.
Area of Science:
- Muscle biology and regenerative medicine.
- Cellular signaling pathways.
- Molecular mechanisms of muscle growth.
Background:
- Transforming growth factor-β (TGF-β) superfamily regulates cellular growth and differentiation.
- Myostatin, a TGF-β member, inhibits muscle growth and is a therapeutic target.
- Smad7 antagonizes TGF-β signaling, influencing myostatin pathways.
Purpose of the Study:
- To investigate the in vivo effects of Smad7 deficiency on muscle growth, differentiation, and regeneration.
- To elucidate the role of Smad7 in modulating myostatin signaling.
- To assess Smad7 as a potential therapeutic target for muscle disorders.
Main Methods:
- Studied Smad7-deficient (Smad7(-/-)) mice.
- Analyzed muscle mass, fiber type, and muscle strength.
- Assessed muscle regeneration and satellite cell activity in vivo and in vitro.
- Measured myostatin expression levels.
Main Results:
- Smad7(-/-) mice exhibited reduced muscle mass, hypotrophy, and fiber type switching.
- Force generation was significantly decreased in Smad7-deficient mice.
- Muscle regeneration and satellite cell proliferation/differentiation were impaired.
- Myostatin expression was upregulated in Smad7(-/-) muscle.
Conclusions:
- Smad7 is a critical regulator of muscle growth and regeneration in vivo.
- Loss of Smad7 leads to increased Smad2/3 signaling, impeding muscle development.
- Smad7 represents a potential intracellular therapeutic target for treating muscle disorders.
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