RANKL signaling drives skeletal muscle into the oxidative profile

Area of Science:

• Molecular Biology
• Skeletal Muscle Physiology
• Bone-Muscle Axis

Background:

• The bone-muscle unit involves reciprocal regulation between bone and muscle.
• Receptor activator of nuclear factor kappa-B ligand (RANKL) influences mitochondrial function in osteoclasts and adipocytes.
• The role of RANKL in skeletal muscle fiber metabolism is not well understood.

Purpose of the Study:

• To investigate the impact of RANKL on skeletal muscle mitochondrial biogenesis and function.
• To elucidate the signaling pathways involved in RANKL-mediated effects on muscle.

Main Methods:

• Utilized C2C12 myotubes for in vitro studies.
• Employed RNA-sequencing and Western blotting to assess mitochondrial biogenesis pathways.
• Quantified mitochondrial DNA and used MitoTracker staining to evaluate mitochondrial content.
• Administered RANKL via mini-osmotic pump in wild-type mice.
• Analyzed soleus muscle respiratory rates in OPG knockout and wild-type mice.

Main Results:

• RANKL stimulation activated mitochondrial biogenesis pathways in myotubes.
• RANKL increased mitochondrial reticulum expansion and boosted spare respiratory capacity.
• RANKL signaling in muscle involves ERK and p38 pathways.
• Mice with altered OPG levels exhibited higher muscle respiratory rates.
• RANKL infusion in wild-type mice enhanced mitochondrial number, respiratory rate, succinate dehydrogenase activity, and fatigue resistance.

Conclusions:

• RANKL plays a significant role in regulating skeletal muscle fiber metabolism.
• RANKL acts as an osteokine-like protein influencing muscle mitochondrial function and performance.
• Targeting RANKL may offer therapeutic potential for muscle-related disorders.