Differentially disrupted spinal cord and muscle energy metabolism in spinal and bulbar muscular atrophy

JCI Insight, 2024 · DOI: https://doi.org/10.1172/jci.insight.178048 · Published: March 7, 2024

Simple Explanation

This study investigates the potential of nicotinamide riboside (NR), an NAD+ precursor, to treat spinal and bulbar muscular atrophy (SBMA) in a mouse model. SBMA is a neuromuscular disease with metabolic disturbances, and previous research suggested that increasing SIRT1 activity could be therapeutic. The researchers found that NR supplementation did not improve motor function or muscle pathology in SBMA mice. Further analysis revealed reduced NAD+ and ATP levels in the muscle, but not in the spinal cord, of SBMA mice, and NR treatment failed to restore these levels. The study suggests that the ineffectiveness of NR might be due to decreased levels of nicotinamide riboside kinase 2 (NRK2), an enzyme necessary for NR to enter the NAD+ salvage pathway, which is critical for cellular energy production.

Study Duration

26 weeks

Participants

Male nontransgenic and AR112Q mice

Evidence Level

Not specified

Key Findings

1
NR supplementation failed to ameliorate motor dysfunction or muscle pathology in a transgenic mouse model of SBMA.
2
NAD+ and ATP levels are substantially reduced in the muscle but not in the spinal cord of SBMA mice, and NR treatment did not restore these levels in the muscle.
3
Metabolomic and proteomic analyses revealed altered metabolic pathways in the quadriceps muscle of SBMA mice, including the NAD+ salvage pathway, with decreased mRNA levels of Nmrk2.

Research Summary

This study evaluated the therapeutic potential of nicotinamide riboside (NR) supplementation in a transgenic mouse model of spinal and bulbar muscular atrophy (SBMA). The researchers aimed to increase SIRT1 activity, which has shown promise in treating metabolic disorders associated with SBMA. The results indicated that NR supplementation did not improve motor dysfunction or muscle pathology in SBMA mice. Further investigation revealed reduced NAD+ and ATP levels in the muscle of SBMA mice, which were not restored by NR treatment. Metabolomic and proteomic analyses suggested that the ineffectiveness of NR might be due to decreased levels of nicotinamide riboside kinase 2 (NRK2), limiting NR's entry into the NAD+ salvage pathway. This highlights the tissue-specific metabolic disruptions in SBMA and the limitations of dietary NAD+ precursor supplementation.

Practical Implications

Therapeutic Strategy

Increasing NAD+ levels in SBMA muscle with the ideal NAD+ precursor and/or delivery method could have a protective effect.

Targeting Skeletal Muscle

Selective targeting of skeletal muscle in SBMA mice ameliorated the hallmarks of disease and highlighted the importance of skeletal muscle in both the pathogenesis and treatment of SBMA.

Further Research

Further experimentation will be necessary to determine which step(s) of NAD+ production are impaired in the muscle of SBMA mice, whether these processes remain intact in the CNS, and if, within the CNS, motor neurons are specifically vulnerable to disrupted energy homeostasis.

Study Limitations

1
NR treatment did not affect AR aggregation in SBMA mice
2
NR treatment had no effect on the blood glucose levels of SBMA mice
3
Decreased levels of Nmrk2 may limit the phosphorylation of NR and prevent its entry into the NAD+ salvage pathway

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