Dysinnervation

Neurogenic changes include denervation, "dysinnervation," and reinnervation. While these are not restricted to older persons, they are the most common pathologic changes found in the atrophying muscle of aging persons. 

This is our hypothetical concept of only partially impaired, incomplete loss of neural influence, especially of molecular neurotrophic factors, some of which are still able to be produced from crippled but alive motor neurons. Our putative "dysinnervation" phenomenon can be conceptualized as having some aspects similar to a persistence of the early stages of ordinary "recent denervation," to which it appears histochemically similar. 

Pan-denervations and pan-dysinnervations in regard to type-2 fiber atrophy... 

These are postulated as adversely influencing mainly the type-2 fibers (or sub-preferentially the type-2B fibers). Hypothetically, "pan-denervations" are due to (a) abnormality of both type-2 and type-1 LMNs or of their intimately related, respectively type-2 and type-1 Schwann cells (which are nurturing the LMNs and being nurtured by them). This results in lack of trophic influence on "all" the muscle fibers, either (i) fully (in pan-denervations) or (ii) partially deficient - quantitatively or qualitatively - (in pan-dysinnervations), to which the type-2 muscle fibers (or sub-preferentially type-2B fibers) are more susceptible or (b) hypothetically, relatively selective abnormality at the level of the presumed type-2 LMNs, or of their closely associated Schwann cells that we designate as "type-2 (or type-2B) Schwann... 

Accordingly, the neurogenic kind of type-2 fiber atrophy is proposed to be a dysinnervation evolving into denervation. 

Both type-2 fiber atrophy (which often seems to be due to dysinnervation) and recent denervation (with or without established reinnervation) exist concurrently in muscle biopsies of many aging patients (see details above and below). 

In each of these four situations, the disorder of each individual cell involved (LMN or Schwann cell) can be complete (resulting in denervation) or partial (resulting in dysinnervation). 

Neurogenic "susceptibUization " in individual persons with elder-atrophy," it is unknown whether or not hypothetical denervation or dysinnervation is occurring and susceptibihzing the musde fibers to undergo atrophy from a concurrent myopathic mechanism. 

If, as we postulate, there is a significant neuropathic component in "sarcopenia," analyses of homogenized muscle are actually looking only at the train wreck but not seeking the upstream cause of the derailment. If a denervation/dysinnervation component is indeed present, that would require moving the focus of pathogenic interest and analysis upstream to the LMNs, their Schwann cells, and possibly to their pre-synaptic afferent neurons. 

As "disease-controls" for biochemical/molecular-genetic studies of muscle atrophy of aged animals, the same investigative techniques should be utilized to examine in mid-adult-age animals the effects of (a) induced acute denervation, slow denervation and dysinnervation and (b) hyponutrition/cachexia. 

How could one ever prove that there is not a neuropathic denervation-dysinnervation component underlying some or many examples of the type-2 fiber atrophy in aged animals, or humans ... 

Denervation and dysinnervation abnormalities are usually neurogenous (but, atypically, sometimes can be myogenous see Chapter 1). Conceptually, denervation is a complete loss of neural influence on the muscle fiber (which initially can be reversible by... 

Denervation/neuropathic aspects-, denervation" can be (a) an anatomic disconnection or (b) only a dysfunctional, partial loss of neuronal trophic influence of the lower motor neuron axon to the denervated muscle fiber, i.e. a dysinnervation (see above). 

Type-2 muscle fiber atrophy can be cansed by varions abnormalities, snch as cachexia, hypoactivity (disnse), glncocorticoid excess, hyperparathyroidism, a manifestation of recent pan-deinnervation [51, 52] or pan-dysinnervation, or npper-motor-nenron abnormality (for extensive discnssion, see Chapter 1). 

Comment A common association of type-2 fiber atrophy (discussed in Chapter 1) is an aspect of a lower-motor-neuron abnormality resulting in functional "dysinnervation," as may be part of the pathogenic mechanism in this patient. Note that routine diagnostic EMG cannot quantify the size of the type-2 muscle-fiber fast-twitch units because they are activated only by vigorous contraction, whereas slow-twitch type-1 motor-units are activated by... 

In our cultured muscle fibers of h-IBM due to a GNB mutation, the presumably genetically determined increase of A 3PP/A 3 preceded other IBM-type abnormalities [221], including (a) their inability to become properly innervated by normal fetal spinal cord neurons, and (b) having morphologically abnormal NMJs [221]. We therefore postulated that spontaneous A 3PP/A 3 overexpression in s-IBM patient muscle may be responsible for a "myogenous dysinnervation" [221] and for the observed NMJ structural abnormalities [220] (see above), and, by analogy, the same A 3PP/AP-based mechanism may be occurring in h-IBM. 

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