Systemic administration of insulin‐like growth factor decreases motor neuron cell death and promotes muscle reinnervation

Abstract

Neonatal sciatic nerve axotomy causes motoneuron death and muscle denervation atrophy. The aim of the present study was to determine whether insulin-like growth factor-I (IGF-I) administration promotes muscle reinnervation and counteracts motor neuron loss after such an injury. Six weeks after sciatic nerve axotomy performed in 2-day-old pups, the number of motor neurons, as assessed by retrograde transport of horseradish peroxidase injected into the extensor digitorum longus (EDL) muscle, was reduced from 52 +/- 3 to 26 +/- 3. Subsequent administration of IGF-I at the doses of 0.02 mg/kg or 1 mg/kg increased the number of motor neurons to 35 +/- 2 and 37 +/- 5, respectively. The effect on motoneuron survival was accompanied by improved muscle fibre morphometry and restoration of indirect EDL muscle isometric twitch tension, which was about 80 % of control values for both doses of IGF-I compared with 60% observed with saline treatment. Reinnervated EDL muscle from saline-treated rats cannot hold tetanic tension, which is, however, achieved after IGF-I treatment at either dose. Thus, both high and low doses of IGF-I counteracted motoneuron death and improved muscle reinnervation following neonatal sciatic nerve axotomy. IGF-I at 5 microg/kg failed to increase muscle reinnervation.

Functional muscle regeneration with combined delivery of angiogenesis and myogenesis factors

“…After muscle injury, an inflammatory response is activated, but prolonged accumulation of fibrotic tissue limits muscle cell replacement, leading to less strength and functional depletion compared with normal muscles. The increased force observed in muscles with GFs delivery may also be related to enhanced reinnervation, although the specific mechanisms by which these GFs influence reinnervation remain to be defined (53,54).…”

The Neuromuscular Junction: Aging at the Crossroad between Nerves and Muscle

“…In accordance with this hypothesis, in mouse models, the overexpression of muscle-specific IGF-1 reverses sarcopenia (Musaro et al, 2001), prevents the age-dependent decrease in type IIB and increase in type IIA fibers (Messi and Delbono, 2003), and also leads to improved nerve regeneration by acting on axons, Schwann cells, and the NMJ. Systemic administration of IGF-1 decreased motor neuron cell death and promoted muscle re-innervation after injury in young animals, suggesting that the decline in IGF-1 with aging may impair the ability of aging animals to repair and maintain the integrity of NMJ (Vergani et al, 1998). IGF-1 sensitivity may not decrease with age, so that IGF-1 could promote regeneration after nerve injury even in older individuals.…”

Neural control of aging skeletal muscle

“…For example, in young rodents IGF-1 expression is up-regulated in Schwann cells and astrocytes following spinal cord and peripheral nerve injury, while IGF-binding protein 6 is strongly upregulated in injured motorneurones (Hammarberg et al, 1998 Interestingly, in regions of muscle enriched with neuromuscular junctions, IGF-II exhibited prominent up-regulation in satellite and possibly glial cells during recovery from sciatic nerve crush (Pu et al, 1999) while IGF-I showed less significant changes. In young animals, systemic administration of IGF-1 decreases lesion-induced motor neurone cell death and promotes muscle re-innervation (Vergani et al, 1998). IGF-1 also promotes neurogenesis and synaptogenesis in diverse areas of the central nervous system such as the hypocampal dentate gyrus during postnatal development (O'Kusky et al, 2000) or increases proliferation of granule cell progenitors (Ye et al, 1996).…”