Nicotinamide riboside prevents mitochondrial dysfunction in nemaline myopathy type 6

Area of Science:

• Biochemistry
• Genetics
• Mitochondrial Biology

Background:

• Nemaline Myopathy type 6 (NEM6) is a congenital myopathy linked to KBTBD13 gene variants.
• Patients often present with skeletal muscle weakness and hypercontractility, with histological evidence suggesting mitochondrial dysfunction.

Purpose of the Study:

• To investigate the role of mitochondrial dysfunction in NEM6 pathology.
• To evaluate nicotinamide riboside (NR) as a potential therapeutic agent to improve mitochondrial function in NEM6.

Main Methods:

• A natural history study was conducted using homozygous Kbtbd13R408C-knockin mice (NEM6 model).
• Methods included high-resolution respirometry, metabolic treadmill tests, histoenzymatic stainings (NADH, SDH), and multi-omics analyses.
• NR supplementation was administered for eight weeks to assess its preventative effects.

Main Results:

• NEM6 mice exhibited decreased mitochondrial respiration, impaired metabolic performance, and core formation with altered histoenzymatic reactions.
• Multi-omics data indicated significant impact on the TCA cycle and reduced NAD+ levels.
• NR treatment in young NEM6 mice successfully prevented the onset of mitochondrial dysfunction.

Conclusions:

• Mitochondrial dysfunction, characterized by impaired respiration and TCA cycle disruption, is a key feature in NEM6 progression.
• Restoring NAD+ levels with NR demonstrates a promising therapeutic avenue for NEM6 by preventing mitochondrial deficits.