The effects of testosterone and insulin-like growth factor 1 on motor system form and function

Abstract

In this perspective article, we review the effects of selected anabolic hormones on the motoric system and speculate on the role these hormones may have on influencing muscle and physical function via their impact on the nervous system. Both muscle strength and anabolic hormone levels decline around middle age into old age over a similar time period, and several animal and human studies indicate that exogenously increasing anabolic hormones (e.g., testosterone and insulin-like growth factor-1 (IGF-1)) in aged subjects is positively associated with improved muscle strength. While most studies in humans have focused on the effects of anabolic hormones on muscle growth, few have considered the impact these hormones have on the motoric system. However, data from animals demonstrate that administering either testosterone or IGF-1 to cells of the central and peripheral motor system can increase cell excitability, attenuate atrophic changes, and improve regenerative capacity of motor neurons. While these studies do not directly indicate that changes in anabolic hormones contribute to reduced human performance in the elderly (e.g., muscle weakness and physical limitations), they do suggest that additional research is warranted along these lines.

1. Introduction

Forty-two percent of the 37.3 million older adults in the United States report having one or more physical limitations performing daily tasks that are essential for maintaining independent living (Seeman et al., 2010). By 2030, this age group is expected to increase to approximately 71.5 million, representing 20% of the U.S. population (CDC, 2008).With the increase in the aging population, weakness and associated conditions (e.g., sarcopenia, dynapenia and frailty) in the elderly are a growing concern. For instance, a loss of voluntary muscle strength predisposes elders to a 4-fold increase in functional limitations and a 2-fold increase in mortality (Manini et al., 2007).While most studies examining weakness with aging have examined the role of skeletal muscle atrophy (Visser et al., 2005, Newman et al., 2006, Manini et al., 2007), other findings suggest that alterations in the aging nervous system also underlie loss or inconsistencies in muscle function (e.g., strength & power) (Laidlaw et al., 2000, Kido et al., 2004, Christie and Kamen, 2006, Clark and Taylor, 2011, Manini and Clark, 2012). In phase with the declines in neuromuscular function is the decline in hormone levels with aging, particularly several circulating factors thought to have anabolic effects (e.g., steroid hormones, growth hormone, and IGF-1). While a majority of studies in humans have independently examined age-related changes in endocrine and nervous system functions, few have integrated these separate concepts to identify possible neuroendocrine changes associated with aging that influence the motoric system (defined herein as the central and peripheral components of the nervous system specific to muscle force generation and control), which could conceptually serve as a mechanistic underpinning of the reduced muscle function, and arguably physical function, observed with advancing age. Human studies examining increased muscle strength and physical function with elevated endogenous hormone levels or exogenous hormone replacement have examined muscle function, but to our knowledge, none have placed particular emphasis on endocrine actions on components of the motoric system. Conversely, most human studies examining the effects of steroids on the nervous system have mostly examined cognitive outcomes without particular emphasis on the motor system or physical function and/or strength. Thus, a gap exists in the literature for human studies examining the role of anabolic hormones (testosterone and insulin-like growth factor 1) on the motor system with respect to declining muscle and physical function with aging. Herein, we present a perspective article on the effects of selected anabolic hormones on the motoric system form and function to raise awareness, and increase discussion, of the potential role that anabolic hormones may have on influencing muscle and physical function via their impact on the human nervous system. Although not heavily examined in humans, we review the few studies in the human literature that have examined the role of anabolic hormones on the motoric system. We also cite relevant studies from the robust body of non-human animal work that have examined the neuroprotective and/or neuroregenerative roles of testosterone and insulin-like growth factor 1 (IGF-1) on the motoric system, and the translational implications from animals to humans will be discussed.

2. The potential role of hormones in the aging motoric system

It is widely accepted that nervous system functions decline in humans with aging, particularly in the cognitive domains, which are reviewed elsewhere (Jagust, 2013, Samson and Barnes, 2013). Separate studies have also indicated age-related functional declines in the human motor system at the levels of the cortex, spinal cord, and motor neurons (Wagman and Lesse, 1952, Kido et al., 2004, McGinley et al., 2010, Kaya et al., 2013, Yao et al., 2014). In the cortex, a cross-sectional study of magnetic resonance brain images of living individuals ranging in age from 18 to 93 years suggests that cortical thinning occurs by middle age with areas near the primary motor cortex showing prominent atrophy (Salat et al., 2004), and a cross-sectional analysis of human cadavers who died without neurological signs found a 43% volumetric reduction in the premotor cortex neuron perikaryon size in individuals over 65 years of age in comparison to adults younger than 45 years (Haug and Eggers, 1991). In addition to anatomical and morphometric changes to the cortex, functional measures are also altered with aging. We have observed that motor cortical excitability is reduced in older adults when compared to young adults (McGinley et al., 2010), and recently reported that weaker seniors have reduced motor cortical excitability (specifically, higher levels of long-interval intracortical inhibition, which is classically believed to be mediated by GABA_B-mediated inhibition) when compared to their stronger counterparts (Clark et al., 2014, Abstract proceeding from International Conference on Frailty and Sarcopenia, Barcelona, Spain). Differences in brain region activation with motor tasks have also been observed in older adults, when compared to young adults, as fMRI measurements indicate that there is less lateralization of activated brain regions (Mattay et al., 2002), and this change is evident during both concentric and eccentric contractions (Yao et al., 2014). Functional decreases in spinal excitability, assessed via the H-reflex, have been reported with advancing age in humans (Kido et al., 2004). Additionally, declines in peripheral motor neuron anatomy and physiology have been observed. More specifically, nerve conduction velocity decreases in humans around the 5th decade (Wagman and Lesse, 1952), while motor neuron loss starts around the 6th decade (Tomlinson and Irving, 1977), arguing for a possible neural mechanism of weakness in the elderly although it should be noted that the results from Tomlinson and Irving have not been replicated in animals due to their use of non-stereological techniques (Tomlinson and Irving, 1977). Power declines are apparent in the upper and lower extremities by age 40 years, and strength declines occur between 50 and 60 years with a much more rapid rate of loss occurring after 60 years (Deschenes, 2004), which is in line with the observations of decreased nerve conduction and motor neuron loss. Our recent findings also suggest an interrelationship between functioning motor unit number and muscle strength in older adults with a reduced number of estimated functioning motor units being related to muscle weakness (Kaya et al., 2013). Thus, it is clear that with advancing age there is a plethora of form and function changes in the motoric system, and it is likely that these changes are linked to impairments in physical performance.

In addition to the age-related motoric system changes, decreases in hormone production occur in a similar time frame with studies indicating low testosterone levels correlating to higher rates of sarcopenia or fall risks in men (Szulc et al., 2004, Orwoll et al., 2006). Do the declines in hormones/circulating factors mediate declines in the motor system? Evidence from animal parabiosis studies suggest that linking the circulatory systems of young mice and old mice enhances skeletal muscle regenerative capacity in old mice with no detectable negative effects in young mice (Conboy et al., 2005). The evidence for circulating factors has also been replicated as blood from young mice injected into old mice improves motor performance (Sinha et al., 2014). In addition to possible influences on muscle tissue, recent evidence has emerged indicating that circulating factors also have a profound influence on the nervous system, as Villeda et al. observed improved cognitive function in old mice injected with serum from young mice, while Ruckh et al. observed remyelination is enhanced in older mice via parabiosis with young mice (Ruckh et al., 2012, Villeda et al., 2014). Taken together, the data suggest the decline of circulating factors with aging may be a critical mechanism driving age-related alterations in the motor system. These data also raise the question of “Which hormone(s) (or other circulating factors) exert effects on the motor system?” In the following sections, we review the current literature with a critical eye on whether testosterone and/or insulin-like growth factor 1 (IGF-1) impact motor system form and function. Although growth hormone (GH) levels have a positive relationship with IGF-1 levels, discussion of GH function on the motoric system will not be specifically discussed herein due to the relatively limited number of investigations examining the effects of GH on the motoric system.

3. Testosterone Synthesis and Actions on the Motoric System

With advancing age in men, free and total testosterone begin to decrease between the third to fifth decade of life, and this decline continues progressively thereafter (Harman et al., 2001). Additionally, endogenous testosterone release pulses are lower in frequency and amplitude at night in middle-aged men compared to young men (Luboshitzky et al., 2003). Because animal and human research has suggested that testosterone is neuroprotective and exerts effects at a variety of the motoric segmental levels (i.e., the brain, spinal cord and motor neurons, etc.) (Bialek et al., 2004, Fargo et al., 2009), it is likely that age-related testosterone decline may lead to declines in strength and physical performance via the motoric system. The interpretation of the data in women is preliminary because of the limitations of total and free testosterone assays. A task force appointed by the Endocrine Society published a position statement emphasizing that T values across the lifespan in women are not accurate (Rosner et al., 2007). However, a study using a validated liquid chromatography-tandem mass spectrometry (LC–MS/MS) method for measuring T reported T levels were 1.8 times higher in pre-menopausal women with an average age of 35 years compared to post menopausal women with an average age of 59 years (Rothman et al., 2011).

In animals, the effects of testosterone on the neuromuscular system have been studied, perhaps most extensively, in the spinal nucleus of the bulbocavernosus (SNB) (Breedlove and Arnold, 1980). In male rats, the SNB is a pool of around 200 motor neurons that innervate the bulbocavernosus (BC), levator ani, and the external anal sphincter (Breedlove and Arnold, 1980, 1981, Schroder, 1980, McKenna and Nadelhaft, 1986). In female rats, the perineal musculature is greatly reduced, and the SNB contains around a third of the motor neurons in males that primarily innervate the external anal sphincter (Breedlove and Arnold, 1981, McKenna and Nadelhaft, 1986, Ueyama et al., 1987). Testosterone establishes the sex difference early by preventing normal cell death as prenatal block of androgen receptors (AR) with the anti-androgen flutamide in males results in the loss of the motor neuron pool (Breedlove and Arnold, 1983a) while perinatal testosterone propionate treatment of females preserves the nucleus (Breedlove and Arnold, 1983b, Nordeen et al., 1985, Sengelaub and Arnold, 1986). The early regulation of SNB motor neuron number is thought to be due to testosterone action on the target musculature as the motor neurons, themselves, lack AR expression in newborn rats and do not express AR until P10 (Fishman et al., 1990, Jordan, 1997). In adulthood, testosterone manipulation affects the size of the cells in the motor neuron pool rather than the numbers. In males rats, castration at 60–80 days of age decreases soma size while testosterone treatment of females increases soma size, but not to the extent seen in males (Breedlove and Arnold, 1981). By this time, AR is expressed on SNB motor neurons (Jordan, 1997) and may directly regulate soma size (Watson et al., 2001). An important observation in the SNB is that normal aging in rodents leads to a decline in testosterone and AR expression on the motor neurons (Matsumoto and Prins, 1998), likely underlying in the shift towards decreased motor neuron soma size within the nucleus from 9 to 22 months of age (Fargo et al., 2007) and the decrease in sexual behavior with age (Larsson, 1958). However, the changes are reversible as testosterone treatment of aged animals restores the SNB motor neuron size distribution observed in young rats (Fargo et al., 2007). There is also evidence that testosterone treatment initiates electromyogram (EMG) burst activities in the BC muscle within minutes of injection into castrated male rats (n = 6/8; aged 8–10 months; castrated at 3 months), a physiological response that the authors attributed to steroid-sensitive neuronal membrane receptors (Sachs and Leipheimer, 1988). Taken together, the motor neuron is a likely site of action for testosterone in the adult androgen-sensitive rodent neuromuscular system and suggests that such androgen responses could occur in motor neurons innervating human muscles. Furthermore, aging could result in a decline of the neuroprotective properties of testosterone in motor neurons.

The SNB findings in rodents are specific to motor neurons whose survival in early development is mediated by AR. However, ARs are found in all spinal motor neurons of adult male and female rats (Sar and Stumpf, 1977, MacLusky et al., 1987, Lumbroso et al., 1996), which confer other important androgen-mediated properties to motor neurons. Cranial nerves contain androgen receptor mRNA and protein (Yu and McGinnis, 1986, Drengler et al., 1996) and are another well-studied model of androgenic neuroprotection on rodent motor neurons. Unlike the SNB, there seems to be no sexual dimorphism in adult neuron numbers in spite of 50% lower AR binding in female rats relative to males (Yu and McGinnis, 2001). However, gonadectomy in male hamsters decreases AR mRNA levels by approximately 50%whereas gonadectomy has no effects on females (Drengler et al., 1996). Additionally, AR binding decreases with age in the facial motor neurons, and the hypoglossal nuclei, in particular, exhibits a decrease in neuron number in 20 month old male rats compared to 4 month old male rats (McGinnis and Yu, 1995). Accordingly, studies in rodent facial nerves may be a useful translational model for age-related issues with strength and motor performance in humans. In the injury paradigm, the neuroprotective role of testosterone is indicated by data showing the regenerative speed of facial motor neurons following injury are significantly faster in young adult male rats in comparison to females and castrated males (Yu, 1982). This study also suggested it is testosterone, and not estradiol, that likely mediates the neuroprotective effects in the nerves. Subsequent studies have confirmed testosterone propionate administration to crushed motor neurons can accelerate facial nerve crush recovery (measured as mm outgrowth per day) in male golden hamsters, and a similar effect was also observed in female hamsters in the same study (Kujawa et al., 1991). With facial nerve crush, animals display unilateral facial paralysis with drooping of one corner of the mouth, flattened and paralyzed vibrissae, and loss of eyeblink reflex, but testosterone treatment in these rodents results in a return of movement during a 2–3 week postoperative period, indicating a functional recovery with the androgen-mediated neuroregeneration (Jones, 1994).

In motor neurons innervating the lower limb, androgen-mediated neuroprotection is observed in the sciatic nerve of rodents as it also expresses AR protein and mRNA (Jordan et al., 2002), and neuroregeneration is observed in the motor neuron axons (Kujawa et al., 1993, Brown et al., 1999) and soma (Tehranipour and Moghimi, 2010). After sciatic nerve crush in male rats, testosterone propionate administration slightly enhances the rate of regeneration and the outgrowth distance of the leading axons after 11 days of postoperative observation (Kujawa et al., 1993). Data from rodent studies examining motor neurons innervating the quadriceps muscles also suggest testosterone has a neuroprotective role in the L2 spinal segment. In the presence of the neurotoxin saporin, which results in motor neuron death and somal and dendritic atrophy of nearby surviving motor neurons, testosterone has also been shown to attenuate dendritic atrophy of the quadriceps motor neuron by 65% compared to groups not treated with testosterone (Little et al., 2009). Furthermore, compared to normal untreated specimens, saporin causes 63% dendrite morphology reduction in quadriceps motor neurons of treated female rats. However, testosterone treatment prevents the dendrite atrophy due to saporin such that only 8% of quadriceps motor neuron dendrites are lost, suggesting neuroprotective effects of testosterone are present in female mammals (Wilson et al., 2009). Although these injury models are not a perfect representation of normal aging, they suggest that testosterone exerts a neurotrophic/neuroprotective effect in androgen-responsive motor neurons and may affect motor neuron recovery. In normal aging of rats, changes in lower limb muscles have been examined in the medial gastrocnemius where there is an increase in slow motor units and a decrease in fast fatigue-resistant motor units. With aging, there is also evidence for motor unit denervation/reinnervation and declines in motor nerve conduction velocity (Kanda and Hashizume, 1989). Another anatomic study in rats indicate there is a ~29% decrease in the number of spinal motor units with age in the rat soleus, which results in longer contraction times (Edstrom and Larsson, 1987). These alterations are somewhat similar to the pattern observed in human anatomy and physiology. There is evidence that a process of denervation and reinnervation with aging occurs, resulting in fiber type grouping and a preferential atrophy of type 2 motor units (Doherty et al., 1993, Vandervoort, 2002), and much of the changes in type 2 muscle fibers occur in the lower body but not in the upper body (Grimby et al., 1982). Additionally, aging in men and women is associated with increased cortical threshold for relaxed motor-evoked potentials (MEPs), decreased MEP amplitudes, and delays in central motor conduction times in the foot, but not hand, muscles (Rossini et al., 1992, Tobimatsu et al., 1998). This finding was interpreted as in vivo evidence for different age-related effects on cervical and lumbar motor neurons in humans (Rossini et al., 1992, Tobimatsu et al., 1998). From a conceptual basis, it is plausible that testosterone decreases, particularly for men, may mediate these changes as the fraction of men who have hypogonadal testosterone increases during a similar time frame (Harman et al., 2001).

Further relevance of the animal work to human work is apparent in a few studies. In humans, Bonifazi et al. reported that exogenous administration of human chorionic gonadotropin in healthy males increased testosterone levels and reduced the ‘motor threshold’ (Bonifazi et al., 2004), which represents the amount of brain stimulation (delivered using transcranial magnetic stimulation) required to elicit a response. A reduction in motor threshold is generally interpreted as indicative of an acute increase in the membrane excitability of pyramidal neurons (Maeda and Pascual-Leone, 2003, Ziemann, 2004). Testosterone also improved motor nerve CV after 9 weeks of treatment in an XXYY patient with peripheral neuropathy and low serum testosterone levels (125 mg treatment once a week for 4 weeks, once every 2 weeks for 4 weeks, and once every 3 weeks thereafter) (Izumi and Tsubahara, 2000). It should be noted that these studies were done in young individuals and one with a genetic syndrome, and it is uncertain what the findings would be in healthy, older adults. However, the decade between 50–60 years of age is when declines in motor nerve conduction velocity CV increase (Wagman and Lesse, 1952), and it is possible that the decline in testosterone levels may mediate this process. To our knowledge, no study has examined the effects of testosterone and age on CV. Thus, while findings of this nature are very limited, it does provide some basic proof of concept that testosterone may alter motoric system excitability and function.

With aging, it is generally accepted that motor units (motor neurons and their innervated muscles) are lost during sarcopenia with aging (Drey et al., 2013, 2014). Although correlational, low apparent free testosterone concentration and total free testosterone index has been observed in sarcopenic men (Szulc et al., 2004), and the loss of muscle strength far outweighs the loss of muscle mass with accompanying deterioration of neuromuscular coordination (Hughes et al., 2001). In summary, the evidence indicates that testosterone may exert a neurotrophic effect on androgen-responsive elements of the motor system and warrants further investigation in the aging human population.

4. IGF-1 synthesis and actions on the motoric system

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.

5. Conclusions

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.