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Published on: December 13, 2013
Loss of popdc3 Impairs Mitochondrial Function and Causes Skeletal Muscle Atrophy and Reduced Swimming Ability in
Chen-Chen Sun1,2, Zhang-Lin Chen1, Dong Yang1
1Key Laboratory of Physical Fitness and Exercise Rehabilitation, College of Physical Education, Hunan Normal University, Changsha, Hunan, China.
Background:
The Popeye domain containing 3 (POPDC3) protein is essential for the maintenance of skeletal muscle homeostasis. POPDC3 is a pathogenic variant gene of limb-girdle muscular dystrophy (LGMD), and its variants lead to LGMDR26. At the animal level, zebrafish larvae with popdc3 mutations develop tail curls and muscle atrophy. However, the mechanism of skeletal muscle atrophy induced by POPDC3 variants/loss remains unclear.
Methods:
Eight-month-old male WT and popdc3 mKO zebrafish were used for this research. Loli Track (Denwmark) and Loligo Swimming Respirometer were used to observe the zebrafish's swimming ability. The zebrafish skeletal muscle structure and cross-sectional area (CSA) were observed and counted by transmission electron microscopy (TEM), H&E and wheat germ agglutinin (WGA). Enriched genes and signalling pathways were analysed using RNA sequencing, and the effects of popdc3 mKO on zebrafish skeletal muscle mitochondrial respiration, biogenesis and dynamics were examined to investigate possible mechanisms.
Results:
The swimming ability of popdc3 mKO zebrafish was reduced, and as evidenced by the reluctance to move, fewer movement trajectories, the total distance travelled (p < 0.001), the average velocity of movement (p < 0.001), oxygen consumption (MO2) (p < 0.01), maximum oxygen consumption (MO2max) (p < 0.05), critical swimming speed (Ucrit) (p < 0.01) and relative swimming speed (Ucrit-r) (p < 0.01) were significantly decreased and increased of the exhaustive swimming time (p < 0.01). In addition, loss of popdc3 reduced zebrafish skeletal muscle weight (p < 0.001), muscle/body weight (p < 0.01), myofibre size and CSA (p < 0.01), increased protein degradation (ubiquitination and autophagy) (p < 0.05) and decreased protein synthesis (p < 0.05), suggesting that popdc3 deficiency induces zebrafish skeletal muscle atrophy. Further, popdc3 mKO zebrafish mitochondrial function is reduced, as evidenced by impaired mitochondrial respiration, decreased biogenesis and kinetic imbalance (p < 0.05).
Conclusions:
POPDC3, a Popeye protein, plays an important role in controlling mitochondrial function and skeletal muscle mass and strength. Loss of popdc3 decreases mitochondrial respiration and mitochondrial biogenesis, disrupting kinetic homeostasis, which induces mitochondrial dysfunction and impaired protein turnover (reduced synthesis and increased degradation), leading to zebrafish skeletal muscle atrophy.
Insights
Loss of Popeye domain containing 3 (POPDC3) causes skeletal muscle atrophy in zebrafish by impairing mitochondrial function and protein turnover. This research clarifies the role of POPDC3 in maintaining muscle health and provides insights into limb-girdle muscular dystrophy.
Area of Science:
- Muscle Biology
- Mitochondrial Physiology
- Genetic Disease Mechanisms
Background:
- Popeye domain containing 3 (POPDC3) is crucial for skeletal muscle homeostasis.
- POPDC3 variants are linked to limb-girdle muscular dystrophy (LGMD) type R26 (LGMDR26).
- The precise mechanisms underlying POPDC3 deficiency-induced skeletal muscle atrophy remain unclear.
Purpose of the Study:
- To investigate the functional consequences of popdc3 loss in zebrafish skeletal muscle.
- To elucidate the molecular mechanisms by which POPDC3 deficiency leads to muscle atrophy.
- To examine the impact on mitochondrial function, protein synthesis, and degradation pathways.
Main Methods:
- Utilized eight-month-old male wild-type (WT) and popdc3 mutant knockout (mKO) zebrafish.
- Assessed swimming ability using specialized respirometry equipment (Loli Track, Loligo Swimming Respirometer).
- Analyzed skeletal muscle structure via transmission electron microscopy (TEM), H&E, and wheat germ agglutinin (WGA) staining.
- Conducted RNA sequencing to identify enriched genes and signaling pathways.
- Examined mitochondrial respiration, biogenesis, and dynamics in popdc3 mKO zebrafish.
Main Results:
- Popdc3 mKO zebrafish exhibited significantly reduced swimming performance, including decreased total distance, average velocity, and critical swimming speed.
- Skeletal muscle analysis revealed reduced muscle weight, muscle/body weight ratio, myofiber size, and cross-sectional area (CSA) in popdc3-deficient fish.
- Mitochondrial function was impaired, with reduced respiration and biogenesis, alongside disrupted kinetic homeostasis, increased protein degradation (ubiquitination, autophagy), and decreased protein synthesis.
Conclusions:
- POPDC3 plays a vital role in regulating mitochondrial function, skeletal muscle mass, and strength.
- Loss of POPDC3 leads to mitochondrial dysfunction and impaired protein turnover, ultimately causing skeletal muscle atrophy.
- These findings highlight POPDC3 as a key factor in maintaining muscle integrity and suggest its dysfunction contributes to muscular dystrophy pathogenesis.
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