Delayed Onset Muscle Soreness (DOMS): The Repeated Bout Effect and Chemotherapy-Induced Axonopathy May Help Explain the Dying-Back Mechanism in Amyotrophic Lateral Sclerosis and Other Neurodegenerative Diseases

Abstract

Delayed onset muscle soreness (DOMS) is hypothesized to be caused by glutamate excitotoxicity-induced acute compression axonopathy of the sensory afferents in the muscle spindle. Degeneration of the same sensory afferents is implicated in the disease onset and progression of amyotrophic lateral sclerosis (ALS). A series of “silent” acute compression proprioceptive axonopathies with underlying genetic/environmental factors, damaging eccentric contractions and the non-resolving neuroinflammatory process of aging could lead to ALS disease progression. Since the sensory terminals in the muscle spindle could not regenerate from the micro-damage in ALS, unlike in DOMS, the induced protective microcircuits and their long-term functional plasticity (the equivalent of the repeated bout effect in DOMS) will be dysfunctional. The acute stress invoking osteocalcin, bradykinin, COX1, COX2, GDNF, PGE2, NGF, glutamate and N-methyl-D-aspartate (NMDA) receptors are suggested to be the critical signalers of this theory. The repeated bout effect of DOMS and the dysfunctional microcircuits in ALS are suggested to involve several dimensions of memory and learning, like pain memory, inflammation, working and episodic memory. The spatial encoding of these memory dimensions is compromised in ALS due to blunt position sense from the degenerating proprioceptive axon terminals of the affected muscle spindles. Dysfunctional microcircuits progressively and irreversibly interfere with postural control, with motor command and locomotor circuits, deplete the neuroenergetic system, and ultimately interfere with life-sustaining central pattern generators in ALS. The activated NMDA receptor is suggested to serve the “gate control” function in DOMS and ALS in line with the gate control theory of pain. Circumvention of muscle spindle-loading could be a choice of exercise therapy in muscle spindle-affected neurodegenerative diseases.

Does Compression Sensory Axonopathy in the Proximal Tibia Contribute to Noncontact Anterior Cruciate Ligament Injury in a Causative Way?—A New Theory for the Injury Mechanism

“…It is demonstrated that dual-task (cognitive and gait functions are used at the same time) could induce a more significant stress in the form of an acute stress response and could impair proprioception leading to falls, compared to single task in the elderly [ 35 ]. The author of this paper further suggest that the same result could occur in unaccustomed or strenuous athletic moments when force production is depleted, but cognitive demand derived ASR is induced in order to sustain athletic performance [ 27 , 30 ]. It is important to note, that this translation applies only to the relationship between cognitive demand induced ASR and proprioception in force production depleted dual-task moments, and not on the fall of elderly which is a multifactorial construct.…”

“…We argue that the concomitant burst compression or crush of the axons of the fastest conducting sensory neurons of the periosteum and epiphysis by the same damaging force could contribute to the impairment of proprioception. It should not be forgotten that the proposed signaling, that highlights excessive eccentric force generation by an ASR [ 27 , 30 ], is bone derived as well, and is demonstrated in the form of immediate release of circulating osteocalcin [ 40 ].…”

“…The proprioceptively impaired muscles are weakened against gravity and, due to inertness, the body weight further loads the ACL at near full extension of the knee. We suggest that the exaggerated contraction of quadriceps muscles is caused by the reflexive stabilization of the postural control, induced by the already microinjuried proprioception [ 30 ]. Paradoxically, the exaggerated quadriceps output further increase the load on the ACL [ 9 , 11 ].…”

“…The delayed latency of the medium latency stretch reflex (MLR) of vasti muscles is also implicated in the valgus collapse phase of the NC-ACL injury mechanism, suggesting the contribution of non-muscular mechanoreceptors [ 64 ]. We suggest that the delayed latency of MLR is indicative of impaired proprioception and it could be due to exchange of monosynaptic static encoding of the stretch reflex to polysynaptic ones in order to enhance postural control [ 30 ]. It is noteworthy that this exchange means not only enhanced proprioceptive integrational and compensatory loading on spinal level, but evidently on supraspinal level as well, where visual and sensimotor integration takes place.…”

“…The above mentioned implies that unaccustomed and strenuous fatiguing eccentric exercise, e.g., skiing is a typical one, could increase the risk of NC-ACL injury, as we could see in DOMS inducing exercises. Accordingly, the current authors are proposing that NC-ACL injuries happen under a cognitive demand derived acute stress reaction (ASR) when insufficient force production is unacceptable in unaccustomed and strenuous fatiguing eccentric exercise moments [ 27 , 30 ].…”