Adaptive and maladaptive motor axonal sprouting in aging and motoneuron disease

Abstract

Motor unit (MU) enlargement by sprouting is an important compensatory mechanism for loss of functional MUs during normal aging and neuromuscular disease. Perisynaptic Schwann cells at neuromuscular junctions extend processes that bridge between denervated and reinnervated endplates, and guide axonal sprouts to reinnervate the denervated endplates. In a rat model of partial denervation, high levels of daily neuromuscular activity have been shown to inhibit the outgrowth of sprouts by preventing Schwann cell bridging. In this review, we consider (1) the relative roles of increasing levels of oxidative stress and neuromuscular activity to the destabilization of neuromuscular junctions with age and disease, and (2) how a progressive increase in the neuromuscular activity of declining numbers of functional MUs contributes to the progressive failure of adaptive sprouting and, in turn, to the progressive muscle weakness in the motoneuron diseases of post-polio syndrome and amyotrophic lateral sclerosis. We conclude that there is a time-related progression of MU loss, adaptive sprouting followed by maladaptive sprouting, and continuing recession of terminals during normal aging. The progression is accelerated in motoneuron disease, progressing more rapidly in the post-polio syndrome after prolonged denervation and extremely rapidly in ALS.

ATF3 expression improves motor function in the ALS mouse model by promoting motor neuron survival and retaining muscle innervation

“…5B). Extension of collateral and terminal axonal sprouts is detected in ALS disease, but this sprouting process is usually unable to compensate for loss of axonal connections with muscle (11). In SOD1 G93A mice, quantification of terminal sprouts in the gastrocnemius muscle detected no sprouting at 60 d. The amount of terminal sprouting at 90 and 120 d was similar, with no increase over time (Fig.…”

“…5). Whereas intact motor neurons undergo distal axonal sprouting, this remodeling is insufficient to innervate neighboring denervated end plates and compensate for motor neuron loss, leading to progressive paralysis and death (11). Regardless of whether these deficits in axonal innervation or capacity to sprout arise as a consequence of events in the soma, such as excitotoxicity, endoplasmic reticulum stress, or mitochondrial pathology, or distally at peripheral nerve endings, it is evident from this study that the functional reserve provided by surviving motor neurons is enhanced by mechanisms that increase their axonal integrity, growth, and sprouting and thereby, maintain maximal connectivity with muscle.…”

“…Additional pathological features include neuromuscular junction (NMJ) denervation, axonal degeneration, and abortive collateral sprouting (10,11). The combination of progressive motor neuron cell death and the retraction of axons from NMJs together with an impaired ability of surviving intact axons to generate compensatory axonal collateral sprouts results in progressive irreversible muscle atrophy (2,12,13).…”

Lactate dyscrasia: a novel explanation for amyotrophic lateral sclerosis

“…The magnetic resonance imaging signal intensities of nucleus V, VII, XII, and nucleus ambiguus of these mice show an age-dependent increase starting around day 60, parallel to the first behavioral signs of motoneuron disorder (Angenstein et al, 2004). Also, the age-related progression of motor unit loss, adaptive sprouting (reinnervation of the denervated end plates), maladaptive sprouting, and continuing recession of nerve terminals during normal aging is extremely rapidly accelerated in ALS (Gordon et al, 2004).…”

The influence on sarcopenia of muscle quality and quantity derived from magnetic resonance imaging and neuromuscular properties

“…The relationship between intrinsic contractile changes and extrinsic neuroanatomical factors is not fully appreciated and few studies have attempted to assess both aspects in concert (Campbell et al 1973;Lexell et al 1988). Functioning MUs undergo remodeling throughout the lifespan, but it is not until the process of denervation outpaces reinnervation in old age that a loss of MU integrity and the ensuing substantive loss of muscle fibers occur (Gordon et al 2004). This process could be one of the extrinsic changes to whole muscle affecting MQ (Doherty 2003), but the possible relationship between loss of MUs and MQ has not been explored systematically.…”