Denervation induces mitochondrial decline and exacerbates lysosome dysfunction in middle-aged mice

Area of Science:

• Aging and Muscle Biology
• Mitochondrial Dynamics and Metabolism

Background:

• Skeletal muscle aging involves declining size and function, partly due to mitochondrial dysfunction.
• Motor neuron denervation (Den) contributes to age-related muscle atrophy.
• Aged muscle shows reduced plasticity and blunted responses to activity changes.

Purpose of the Study:

• Compare mitochondrial turnover in young vs. middle-aged mice.
• Investigate the impact of denervation on mitochondrial pathways in aging muscle.
• Determine the onset of blunted muscle plasticity with age.

Main Methods:

• Utilized transgenic mt-Keima mice for mitochondrial tracking.
• Subjected mice to 1, 3, or 7 days of motor neuron denervation.
• Analyzed muscle mass, mitochondrial content, PGC-1α protein, and lysosomal/autophagosomal markers.

Main Results:

• Middle-aged muscle exhibited increased mitochondrial fission and mitophagy, with higher lysosome protein abundance.
• Denervation induced muscle atrophy and reduced mitochondrial protein content by 7 days.
• Denervation led to decreased PGC-1α, elevated autophagosomal/lysosomal proteins, but evidence of lysosome dysfunction in middle-aged mice.

Conclusions:

• Increased fission accelerates mitophagy in middle-aged muscle to preserve mitochondrial quality.
• Denervation exacerbates aging by reducing biogenesis, potentially limited by lysosomal capacity.
• This leads to accumulation of dysfunctional mitochondria and age-related neuromuscular decline.