[h=2] IGF-1 synthesis and actions on the motoric system[/h][h=2]Another anabolic hormone that could have effects on the motoric system is insulin-like growth factor 1 (IGF-1, also known as somatomedin C). Although the neuroprotective properties of IGF-1 are well known in some rodent models of disease (Kaspar et al., 2003, Palazzolo et al., 2009), we will primarily focus on the effects of IGF-1 in aging and injury of the motoric system components. A study in mice suggests a majority (an estimated 75%) of IGF-1 is produced in the liver (Liu et al., 2000), while data from the human population indicates hepatic IGF-1 production is correlated with growth hormone secretion (Rudman et al., 1981). The remaining IGF-1 in the body is extrahepatic, and a study in mouse cell lines suggests IGF-1 is produced locally in tissues to have autocrine/paracrine actions (Tollefsen et al., 1989). With advancing age, cross-sectional studies in men and women indicate serum IGF-1 levels peak in the middle to late teenage years, decreasing sharply shortly thereafter, and decline at a more gradual rate each year starting around the third decade (Brabant and Wallaschofski, 2007), and continues to decline to very low levels until ≥60 years of age in a process known as ‘somatopause’ (Junnila et al., 2013). In the nervous system, IGF-1 is an anti-apoptotic factor during development (Hodge et al., 2007) and also serves as a neuroprotective factor in adulthood by reducing neuronal loss in the nervous system when administered in rats before spinal cord injury (Sharma et al., 1998) and after hypoxic and/or ischemic injury in brain (Guan et al., 1993, Liu et al., 2001).With age-related decline of IGF-1, it is believed that the nervous system and the motoric system lose some regenerative capacity (Apel et al., 2010), potentially leading to a decline in muscle or physical function.
In the cortex, IGF-1 targets high voltage-activated Ca2+ channels to regulate membrane excitability (Shan et al., 2003), and IGF-1 treatment enhances Ca2+ current in motor cortex neurons in senescent rats (Shan et al., 2003). However, the above-referenced study also demonstrated that the Ca2+ channel currents of the neurons from senescent rats have similar voltage dependence and amplitude as those in young adult rats, and it was uncertain from this study whether IGF-1 at the cortical level affected muscle strength or motor unit recruitment. A series of studies in rodents have also documented the neurotrophic effects of IGF-1 on the motoric system (Gao et al., 1999, Ozdinler and Macklis, 2006, Apel et al., 2010). IGF-1 enhances axon outgrowth length of corticospinal motor neurons (CSMN) (Ozdinler and Macklis, 2006). The enhancement results in 2.5–3 times the length observed in vehicle- and brain derived neurotrophic factor (BDNF)-treated CSMNs. Although blockade of IGF-1 reduced axon outgrowth, the CSMNs were still viable, suggesting cell death and axon morphology were dissociated. Data suggest two active isoforms of IGF-1 confer neuroprotection: IGF-1Ea, which is the hepatic or systemic IGF-1, and mechano growth factor (MGF), which is expressed in response to mechanical overload/tissue injury (Yamaguchi et al., 2006). In a rat facial nerve avulsion model, IGF-1Ea- and MGF-preserves 37% and 88% more motor neurons when treated a week before injury compared to the untreated nerve avulsion group, respectively (Aperghis et al., 2004).
At the spinal level, motor neurons express IGF-1 receptors and are protected from glutamate toxicity with IGF-1 treatment in motor neurons from E15 rat embryos (Vincent et al., 2004), although the timing of the treatment is important to recovery (Vincent et al., 2004). In peripheral nerves, IGF-1 staining increases in regenerating nerves of female rats after transection (Hansson et al., 1986), and this effect has been localized to motor neurons of young rats (Hammarberg et al., 1998). Locally delivering IGF-1 in transected tibial nerve of old and young rats results in increased axons per nerve, axon density, and axon diameter (Apel et al., 2010). Furthermore, myelin is also thicker in old and young rats treated with IGF-1 (Apel et al., 2010). This would suggest greater nerve CV is a possibility with higher IGF-1 levels, and this has been demonstrated in an earlier study by examining IGF-1 knockout mice (Gao et al., 1999). Homozygous IGF-1 knockout mice exhibit about half the motor nerve CV seen in wild type mice with normal IGF-1 levels, and heterozygous mice with intermediate levels of IGF-1 have intermediate CV compared to the other two groups. Furthermore, treating IGF-1 knockout mice with IGF-1 increases CV up to wild type levels (Gao et al., 1999). Thus, it may be reasonable to expect that a decline in IGF-1 levels with age in humans may contribute to the slowing in motor nerve CV observed in older adults, but delaying the decline in IGF-1may attenuate the observed decline in motor nerve CV. Similar to the effects of testosterone described above, IGF-1 also allows functional recovery with the attenuation of cell death (Nakao et al., 2001). In a rabbits with spinal cord ischemia, intravenous IGF-1 preserves motor neuron number and terminal deoxynucleotidyltransferase-mediated deoxyuridine triphosphate-biotin nick-end labeling (TUNEL — a marker for cell apoptosis) levels are comparable to sham but less than cells in vehicle- and insulin-treated rabbits (Nakao et al., 2001). Furthermore, hindlimb function after 48 h is maintained in IGF-1 treated animals, which is not observed with vehicle or insulin (Nakao et al., 2001).
Some of the action of IGF-1 on motor neuron survival seems to be mediated by contacting cells. While IGF-1 has muscle-specific actions, such as promoting muscle growth by preventing myofibrillar protein breakdown (Sacheck et al., 2004) and preventing age-related muscle atrophy in older animals (Musaro et al., 2001), some of the actions of IGF-1 are likely due to paracrine effects of muscular IGF-1 on peripheral motor neuron axons to preserve the function of the motoric system as IGF-1 treatment on gluteal muscles of adult mice induces motor neuron axon sprouting (Caroni and Grandes, 1990). IGF-1 overexpression in skeletal muscle prevents age-related loss of specific force (Gonzalez et al., 2003), and muscle-specific IGF-1 also enhances peripheral nerve regeneration after injury (Rabinovsky et al., 2003), indicating a paracrine or target-derived trophic effect of IGF-1. Furthermore, muscle fiber specific force is increased where IGF-1 injected into skeletal muscles is specifically targeted to motor neurons and retrogradely transported by the motor axons back to the motor neuron soma as visualized by immunocytochemistry (Payne et al., 2006). In cases where IGF-1 was not targeted to the motor neurons, no increase in specific force was observed. Cell cultures of newborn mouse motor neurons also suggest that astrocytes can mediate IGF-1 effects on cell survival (Ang et al., 1992). Thus, several pieces of evidence suggest IGF-1 regulates function of the motoric system elements by enhancing regeneration or increasing cell excitability by upregulating Ca2+ channels. Some studies examining muscle function also suggest muscle strength is increased with IGF-1 due to target-derived or paracrine trophic actions from neighboring non-neuronal cells onto the nervous system in mice (Rabinovsky et al., 2003, Payne et al., 2006). Thus, collectively, these findings suggest that IGF-1 may prevent the loss of strength accompanying aging by acting at different levels and by several separate mechanisms in the motoric system.
Conclusions[/h]While only a limited number of human studies have examined the effects of steroids on the motor system, there is growing evidence, from animal studies in particular, that certain anabolic hormones, such as testosterone and IGF-1, exert effects on regenerative ability and anti-apoptotic effects on the central and peripheral tissues of the motoric system. The age-related decline of these hormones have not received significant attention as it relates to whether they mediate age-related changes in the human motor system and how these changes impact the loss of muscle strength and physical function commonly observed in the elderly. However, there is growing evidence for selected anabolic hormones to influence the form and function of the motoric system, and, as such, there is a need for increased research in this area.
