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UCHL1 regulates oxidative activity in skeletal muscle
Hongbo Gao1, Ryan Antony1, Rekha Srinivasan1
1Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, SD, United States of America.
Plos One
|November 2, 2020
Summary
Ubiquitin C-terminal Hydrolase L1 (UCHL1) regulates muscle oxidative metabolism and mitochondrial function. Its absence increases muscle fatigue and reduces key mitochondrial proteins, indicating a novel role in skeletal muscle health.
Area of Science:
- Biochemistry
- Molecular Biology
- Skeletal Muscle Physiology
Background:
- Ubiquitin C-terminal Hydrolase L1 (UCHL1) is a deubiquitinating enzyme primarily known for its role in neurons.
- Recent findings indicate UCHL1 expression in C2C12 myoblast cells and mouse skeletal muscle.
Purpose of the Study:
- To investigate the role of UCHL1 in mouse skeletal muscle, specifically its expression pattern and function in oxidative fibers.
- To determine the impact of UCHL1 deficiency on skeletal muscle oxidative activity, fatigue resistance, and mitochondrial function.
Main Methods:
- Skeletal muscle-specific gene knockout (smKO) of UCHL1 in mice.
- Succinate Dehydrogenase (SDH) staining to assess oxidative activity.
- In situ muscle contraction tests to evaluate fatigue.
- Western blotting and immunoprecipitation to analyze protein levels and interactions (e.g., UCHL1, HSP60, AMPKα).
- Immunostaining for UCHL1 and mitochondrial markers (VDAC).
- Mitochondrial fractionation assays.
Main Results:
- UCHL1 is predominantly expressed in oxidative muscle fibers in mouse skeletal muscle.
- UCHL1 smKO mice exhibited reduced skeletal muscle oxidative activity and increased susceptibility to fatigue.
- Knockout of UCHL1 led to a significant reduction in proteins involved in mitochondrial oxidative phosphorylation.
- UCHL1 co-localizes with the mitochondrial marker VDAC and is found in both cytosolic and mitochondrial fractions.
- UCHL1 interacts with HSP60, a mitochondrial protein transport chaperone, with a trend towards HSP60 downregulation in UCHL1 smKO muscle.
- AMPKα phosphorylation, a regulator of mitochondrial biogenesis, remained unchanged.
Conclusions:
- UCHL1 plays a significant role in maintaining skeletal muscle oxidative metabolism and function.
- UCHL1 may regulate mitochondrial content and oxidative activity through interaction with chaperones like HSP60.
- UCHL1 emerges as a novel regulator of mitochondrial function in skeletal muscle.
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