What is the process by which NAD+ is regenerated in muscles during intense exercise?

The regeneration of NAD+ in muscles during intense exercise occurs primarily through fermentation. During strenuous exercise, when oxygen availability is limited, cells rely on anaerobic pathways to produce ATP. Glycolysis breaks down glucose into pyruvate, generating a small amount of ATP and reducing NAD+ to NADH in the process.

In the absence of sufficient oxygen, the body cannot fully oxidize pyruvate via aerobic respiration, so it converts pyruvate into lactate (or lactic acid) through fermentation. This conversion reoxidizes NADH back to NAD+, allowing glycolysis to continue and produce more ATP, even in low-oxygen conditions.

Although the Cori cycle involves the recycling of lactate back to glucose in the liver and is related to the lactate produced during fermentation, the immediate pathway responsible for regenerating NAD+ in the muscle during intense exercise is fermentation itself. Glycolysis relies on the reoxidation of NADH for sustained ATP production under anaerobic conditions, and that occurs through fermentation.

Aerobic respiration, while efficient for producing ATP in the presence of oxygen, is not the pathway used for NAD+ regeneration during high-intensity activities when oxygen levels are insufficient.