Unaccustomed and/or strenuous eccentric contractions are known to cause delayed-onset
muscle soreness. In spite of this fact, their exact cause and mechanism have been
unknown for more than 120 years. The exploration of the diverse functionality of the
Piezo2 ion channel, as the principal proprioceptive component, and its autonomously
acquired channelopathy may bring light to this apparently simple but mysterious pain
condition. Correspondingly, the neurocentric non-contact acute compression axonopathy
theory of delayed-onset muscle soreness suggests two damage phases affecting two muscle
compartments, including the intrafusal (within the muscle spindle) and the extrafusal
(outside the muscle spindle) ones. The secondary damage phase in the extrafusal muscle
space is relatively well explored. However, the suggested primary damage phase within
the muscle spindle is far from being entirely known. The current manuscript describes
how the proposed autonomously acquired Piezo2 channelopathy-induced primary damage
could be the initiating transient neural switch in the unfolding of delayed-onset
muscle soreness. This primary damage results in a transient proprioceptive neural
switch and in a switch from quantum mechanical free energy-stimulated ultrafast proton-coupled
signaling to rapid glutamate-based signaling along the muscle–brain axis. In addition,
it induces a transient metabolic switch or, even more importantly, an energy generation
switch in Type Ia proprioceptive terminals that eventually leads to a transient glutaminolysis
deficit and mitochondrial deficiency, not to mention a force generation switch. In
summary, the primary damage or switch is likely an inward unidirectional proton pathway
reversal between Piezo2 and its auxiliary ligands, leading to acquired Piezo2 channelopathy.
