NAD depletion in skeletal muscle does not compromise muscle function or accelerate aging, 2025, Sabina Chubanava et al

Highlights•

• Knockout of Nampt in adult mouse skeletal muscle decreases NAD+ by 85%•
• Exercise tolerance and muscle contractility are intact despite NAD depletion•
• A 50% decrease in mitochondrial NAD does not affect mitochondrial structure and function•
• Lifelong depletion of skeletal muscle NAD does not exacerbate muscle aging

Summary
Nicotinamide adenine dinucleotide (NAD) is a ubiquitous electron carrier essential for energy metabolism and post-translational modification of numerous regulatory proteins. Dysregulations of NAD metabolism are widely regarded as detrimental to health, with NAD depletion commonly implicated in aging.

However, the extent to which cellular NAD concentration can decline without adverse consequences remains unclear. To investigate this, we generated a mouse model in which nicotinamide phosphoribosyltransferase (NAMPT)-mediated NAD+ biosynthesis was disrupted in adult skeletal muscle.

The intervention resulted in an 85% reduction in muscle NAD+ abundance while maintaining tissue integrity and functionality, as demonstrated by preserved muscle morphology, contractility, and exercise tolerance.

This absence of functional impairments was further supported by intact mitochondrial respiratory capacity and unaltered muscle transcriptomic and proteomic profiles. Furthermore, lifelong NAD depletion did not accelerate muscle aging or impair whole-body metabolism. Collectively, these findings suggest that NAD depletion does not contribute to age-related decline in skeletal muscle function.
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That’s really interesting!

Explain like I’m brain foggy:

Background

• Out of all the ways for cells to generate ATP, oxidative phosphorylation is the most efficient, meaning that it produces the most ATP per starting “fuel” molecule.
• To do this, the mitochondria horde reducing agents (electrons bound to an H atom) which they then release in a controlled way to convert the energy of their movement into ATP.
• When not actively flowing through the electron transport chains, those reducing agents are “stored” by NAD (becoming NADH) and FAD (becoming FADH2).
  
  
• Since the mitochondria needs to keep its own NADH and FADH2 pools separate from the cytosol, it relies on two “shuttles” to bring in reducing agents.
  
  
• The malate-aspartate shuttle transfers H between NADH pools. The G3P shuttle transfers H between FADH2 pools. NADH and FADH2 pools are both “replenished” at different stages of the TCA cycle.

Main finding:

• This study suggests that even if NAD pools are depleted—think of it like a battery being able to hold less “max” charge—the G3P shuttle gets upregulated to compensate adequately (at least for the case of muscle function in mice).
• [edit: it could also indicate that even if there’s less “storage” available in one form, you only need a certain amount of storage to keep the process going at the level required for activity so long as your shuttle is working as it should]

ME/CFS relevance?

• I find this very interesting since it confirms that in order to actually impair mitochondrial function via the TCA cycle (in a way that couldn’t be compensated for by this mechanism), you’d have to inhibit both NADH and FADH2 turnover steps. Which just so happens to be what would happen if succinate dehydrogenase is being inhibited…
  
  
• Of course they may be differences between humans and mice, though this basic metabolic process tends to be highly conserved across species.