Enhanced pro-BDNF-p75NTR pathway activity in denervated skeletal muscle

Area of Science:

• Neuroscience
• Skeletal Muscle Biology
• Molecular Biology

Background:

• Brain derived neurotrophic factor (BDNF) and its receptors TrkB and p75 neurotrophin receptor (p75NTR) are present in skeletal muscle.
• The precise roles of BDNF, TrkB, and p75NTR in skeletal muscle denervation remain unclear.
• Skeletal muscle denervation, resulting from conditions like spinal cord injury, peripheral neuropathy, and aging, leads to detrimental effects on muscle mass and function.

Purpose of the Study:

• To investigate the involvement of BDNF, TrkB, and p75NTR in the adverse effects of skeletal muscle denervation.
• To elucidate the specific mechanisms by which these factors contribute to muscle atrophy and inflammation following denervation.

Main Methods:

• Utilized a mouse model of unilateral sciatic denervation.
• Quantified protein levels of pro- and mature BDNF, TrkB, and p75NTR via Western blot.
• Assessed downstream signaling pathway activation (JNK, NF-kB) and inflammation using tissue staining.
• Employed a p75NTR inhibitor (LM11A-31) and skeletal muscle-specific BDNF knockout to study the roles of p75NTR and pro-BDNF.

Main Results:

• Denervated muscle showed significant upregulation of pro-BDNF and p75NTR, alongside activation of JNK and NF-kB signaling pathways.
• Muscle atrophy and inflammation were observed in denervated muscles.
• p75NTR inhibition markedly reduced JNK activation and inflammatory cytokine levels in denervated muscle.
• Skeletal muscle-specific BDNF knockout attenuated pro-BDNF levels, JNK activation, and inflammation in denervated muscle.

Conclusions:

• The study demonstrates that pro-BDNF upregulation and p75NTR pathway activation are implicated in denervation-induced skeletal muscle inflammation.
• These findings suggest that targeting the pro-BDNF-p75NTR pathway represents a potential therapeutic strategy for mitigating skeletal muscle inflammation.