Fatigue of muscles weakened by death of motoneurons

Abstract

Weakness is a characteristic of muscles influenced by the postpolio syndrome (PPS), amyotrophic lateral sclerosis (ALS), and spinal cord injury (SCI). The strength deficits relate to changes in muscle use and to the chronic denervation that can follow the spinal motoneuron death common to these disorders. PPS, ALS, and SCI also involve variable amounts of supraspinal neuron death, the effects of which on muscle weakness remains unclear. Nevertheless, weakness of muscle itself defines the functional consequences of these disorders. A weaker muscle requires an individual to work that muscle at higher than usual intensities relative to its maximal capacity, inducing progressive fatigue and an increased sense of effort. Little evidence is available to suggest that the fatigue commonly experienced by individuals with these disorders relates to an increase in the intrinsic fatigability of the muscle fibers. The only exception is when SCI induces chronic muscle paralysis. To reduce long-term functional deficits in these disorders, studies must identify the signaling pathways that influence neuron survival and determine the factors that encourage and limit sprouting of motor axons. This may ensure that a greater proportion of the fibers in each muscle remain innervated and available for use.

Denervation-induced skeletal muscle atrophy is associated with increased mitochondrial ROS production

“…Innervation is critical for growth and maintenance of muscle fibers, and denervation is well known to cause muscle atrophy (36). Denervation is extensively documented in ALS, caused by the degeneration of lower motor neurons (75), whereas independent lines of evidence also attest to denervation (caused by breakdown of neuromuscular junctions) in Sod1 Ϫ/Ϫ mice (25,57,70). With respect to aging, it is understood that sarcopenia is a multifactorial process and that denervation plays a significant role (15,23).…”

“…Motor neurons are known to exert a trophic effect on skeletal muscle, and in the absence of neural activity, muscle mass decreases, along with a reduction in specific force, fiber diameter, and fiber number (6,73). Loss of motor neurons, breakdown of neuromuscular junctions, or inhibition of neural signaling occurs in many neuromuscular diseases, including ALS or spinal cord injury (75), spinal muscular atrophy (56), diabetic neuropathy (72), and aging (6,41,48), and each of these situations is associated with muscle atrophy. It is possible that lack of trophic factors could have a negative impact on muscle mitochondrial function.…”

Motoneuron Death after Human Spinal Cord Injury

“…The contributions of chronic muscle denervation (due to motoneuron death and/or ventral root avulsion) and alterations in muscle use to the striking muscle weakness and atrophy seen after human spinal cord injury also remain unclear. [9][10][11][12][13] Motoneuron death after human spinal cord injury has largely been inferred from physiological signs of muscle denervation, not from morphological analysis. For example, various muscles innervated from the lesion epicenter have been unresponsive to electrical stimulation of their peripheral nerves, consistent with complete muscle denervation.…”

Effect of fluoxetine on disease progression in a mouse model of ALS

“…Furthermore, it is recommended by the European Federation of Neurological Societies to treat depression in ALS patients with amitriptyline, a tricyclic antidepressant, or SSRIs such as fluoxetine (Andersen et al 2005). In addition to depression, ALS patients also suffer from pseudobulbar affect (Gallagher 1989), fatigue (Barthlen and Lange 2000;Francis et al 1999;Lou et al 2003; Thomas and Zijdewind 2006), and muscle weakness (Gourie-Devi et al 2003), which are thought to be due to changes in the serotonergic system and are often also treated with antidepressants (Brooks 2007;Ferraro et al 2000Ferraro et al , 2001Ferraro et al , 2002Ferraro et al , 2005Schiffer et al 1985;Szczudlik et al 1995).…”