Targeted Expression of IGF‐1 Transgene to Skeletal Muscle Accelerates Muscle and Motor Neuron Regeneration

Abstract

Currently, there is no known medical treatment that hastens the repair of damaged nerve and muscle. Using IGF-1 transgenic mice that specifically express human recombinant IGF-1 in skeletal muscle, we test the hypotheses that targeted gene expression of IGF-1 in skeletal muscle enhances motor nerve regeneration after a nerve crush injury. The IGF-1 transgene affects the initiation of the muscle repair process after nerve injury as shown by increased activation of SCA-1positive myogenic stem cells. Increased satellite cell differentiation and proliferation are observed in IGF-1 transgenic mice, shown by increased expression of Cyclin D1, MyoD, and myogenin. Expression of myogenin and nicotinic acetylcholine receptor subunits, initially increased in both wild-type and IGF-1 transgenic mice, are restored to normal levels at a faster rate in IGF-1 transgenic mice, which indicates a rescue of nerve-evoked muscle activity. Expression of the IGF-1 transgene in skeletal muscle results in accelerated recovery of saltatory nerve conduction, increased innervation as detected by neurofilament expression, and faster recovery of muscle mass. These studies demonstrate that local expression of IGF-1 augments the repair of injured nerve and muscle.

Comparative evaluation of IGF-I gene transfer and IGF-I protein administration for enhancing skeletal muscle regeneration after injury

“…Although it has been demonstrated that increased IGF-I levels improve skeletal muscle regeneration after various types of injuries, no study had compared the relative efficacy of various methods of IGF-I delivery to enhance functional recovery. 17,18,[20][21][22] Our findings indicate that IGF-I hastens functional recovery after myotoxic injury, regardless of the route of administration, but that electrotransfer-assisted Figure 4 Mean data for tetanic force production of the TA muscle measured in situ at 7, 14, 21 or 28 days after notexin-induced injury. Four days after myotoxic injury, the TA was injected with 80 mg of a plasmid encoding IGF-I followed by electrotransfer (pIGF-I).…”

“…Studies on transgenic mice have shown that IGF-I overexpression prevents an age-related decrease in skeletal muscle mass and regenerative capacity and that IGF-I enhances skeletal muscle regeneration after myotoxic injury or nerve damage. [15][16][17] Viral-mediated IGF-I delivery prevents the age-related loss of skeletal muscle function and has been shown to promote skeletal muscle hypertrophy in an additive manner when combined with resistance exercise training. 18,19 Non-viral plasmid-based electroporationassisted IGF-I gene transfer has been shown to enhance skeletal muscle regeneration after laceration injury.…”

Angiotensin II as candidate of cardiac cachexia

“…Thus, musclespecific over-expression of IGF-1 has been shown to ameliorate the dystrophic phenotype in the MDX mouse (an animal model for Duchenne muscular dystrophy) [28], and has been shown to accelerate muscle regeneration [29]. IGF-1 binding, which can be modulated via the effects of IGF binding proteins, activates the IGF-1 receptor (IGFR), a receptor tyrosine kinase.…”

Recovery of skeletal muscle mass after extensive injury: positive effects of increased contractile activity

“…Among the numerous growth factors involved at the onset of the regeneration process, IGF-I is known to stimulate satellite cell proliferation and differentiation and to increase muscle protein synthesis (16,41). IGF-I activates the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt) pathway, which is necessary and sufficient to induce skeletal muscle hypertrophy (20).…”