Geoffrey Goldspink

University of London · Surgery and Intervential Sciences: Anatomy and Developmental Biology

Insulin-like growth factor I (IGF-1) is an important peptide synthesized in response to growth hormone stimulation. Alternative promoters and an elaborate alternative splicing regulated in a tissue- and developmentally-specific manner result in the production of several distinct isoforms of IGF-1 [reviewed in Gorecki et al. (2007); Matheny et al. (...

Age-related muscle wasting and increased frailty are major socioeconomic as well as medical problems. In the quest to extend quality of life it is important to increase the strength of elderly people sufficiently so they can carry out everyday tasks and to prevent them falling and breaking bones that are brittle due to osteoporosis. Muscles generat...

Loss of muscle mass and strength is a major problem during aging and the expression of Mechano Growth Factor (MGF), a member of the IGF-1 (insulin-like Growth Factor 1) super family, has been shown to be both exercise and age dependent. MGF, also called IGF-1Ec, has a unique E domain with a 49bp insert in humans (52bp in rodents; IGF-1Eb), which re...

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Insulin-like growth factor I (somatomedin C or mature IGF-I) is an anabolic factor and its overexpression in skeletal muscle promotes muscle mass. Today, a paracrine loop of IGF-mediated cell signaling is seen as the default mechanism for control of muscle mass ([14][1], [34][2]). Concern on this

This article discusses the inevitable use of growth factors for enhancing muscle strength and athletic performance. Much effort has been expended on developing a treatment of muscle wasting associated with a range of diseases and aging. Frailty in the aging population is a major socioeconomic and medical problem. Emerging molecular techniques have...

Growth factors (GFs) act as signalling agents for cells and become a more and more popular mean to influence the human body and its tissues. This review gives an overview of the current possibilities to use such agents in the field of sports related injuries and thus providing the athlete with a whole new potential to minimize recovery time. GFs an...

Insulin-like growth factor-I (IGF-I) is a known biomarker of recombinant human growth hormone (rhGH) abuse, and is also used clinically to confirm acromegaly. The protein leucine-rich alpha-2-glycoprotein (LRG) was recently identified as a putative biomarker of rhGH administration. The combination of an ACN depletion method and a 5-min ultra-high-p...

An integrated MS-based proteomic approach is described that combines MALDI-MS and LC-MS with artificial neural networks for the identification of protein and peptide biomarkers associated with recombinant human growth hormone (rhGH) administration. Serum from exercised males administered with rhGH or placebo was analysed using ELISA to determine in...

In an animal model of ALS, intramuscular administration of MGF, the IGF-I Ec gene splice variant, improved muscle strength and increased both motor unit and motor neuron survival. Here we investigated whether there is a deficit in MGF production in the muscles of patients with ALS. We used complementary in vivo and in vitro techniques to study the...

To investigate the molecular basis of temperature adaptation in natural populations we used the candidate gene approach, targeting the myosin heavy chain (MyHC) gene. The functional effects of genetic variation in MyHC have been well characterised, and changes in the flexibility of the surface loops 1 and 2, caused by modulations in length, amino a...

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by motoneuron degeneration. Although viral delivery of IGF-I has shown therapeutic efficacy in the SOD1(G93A) mouse model of ALS, clinical trials of IGF-I in ALS patients have led to conflicting results. Here we examine the effects of an IGF-I splice variant, me...

Elevated growth hormone (GH) levels lead to increased circulating insulin-like growth factor-I (IGF-I), but the effects on localised muscle IGF-I splice variant expression is not known. The effects of rhGH administration, with or without an acute bout of high resistance exercise, were measured on serum IGF-I and on the mRNA levels of IGF-I splice v...

Recovery from micro damage resulting from intensive exercise has been shown to take longer in older muscles. To investigate the factors that may contribute to muscle repair, we have studied the expression of two splice variants of the insulin-like growth factor-I (IGF-I) gene. IGF-IEa and mechano growth factor (MGF) were studied in response to 1 h...

Recently much interest has been shown in developing a treatment of muscle wasting associated with a range of diseases as well as in ageing, which are major medical and socioecomonic problems. Emerging molecular techniques have made it possible to gain a better understanding of the growth factor genes involved and how they are activated by physical...

The aim of this study was to investigate effects of albumin and insulin separately as well as in combination on mature muscle fibres during long-term culture. Single muscle fibres were dissected from m. iliofibularis of Xenopus laevis and attached to a force transducer in a culture chamber. Fibres were cultured in a serum-free medium at slack lengt...

Mechano-growth factor (MGF) is a splice-variant of IGF-I sharing an identical mature region, but with a different E domain. Our objective was to determine if MGF would reduce the area of 'at-risk' myocardium and improve cardiac function in the post-infarct heart. Infarcts were induced by injection of microspheres. In experiment 1, sheep were treate...

IntroductionGrowth hormone-IGF-I axisExpression of IGF-I splice variants in muscleMechano growth factorSystemic IGF-I is produced by active muscleThe structure of IGF-IReceptors mediate the cellular effects of IGF-IIGF-I binding proteinsBiological action of the IGF-I splice variantsGenetic manipulation of IGF-I in muscleGene transfer of the differe...

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Age-related muscle wasting and increased frailty is a major socioeconomic as well as a major medical problem. In our quest to extend the quality of life it is important to increase the strength of elderly people sufficiently so they can carry out everyday tasks and prevent them falling and breaking bones that are brittle because of osteoporosis. Mu...

Insulin-like growth factor (IGF)-I induces proliferation of transformed cells. Its binding proteins (IGFBP) are involved in local regulation of IGF. This study assessed the effects of overexpression of IGFBP-4 on the development of cancer in vivo. Nude mice were subcutaneously inoculated with HT-29 colorectal cancer cells (3 x 10(6)). When the tumo...

The effects of muscle splice variants of insulin-like growth factor I (IGF-I) on proliferation and differentiation were studied in human primary muscle cell cultures from healthy subjects as well as from muscular dystrophy and ALS patients. Although the initial numbers of mononucleated progenitor cells expressing desmin were lower in diseased muscl...

Insulin-like growth factors are known to inhibit apoptosis and promote tumour angiogenesis. Previously we have shown that insulin-like growth factor binding protein-4 (IGFBP-4) gene therapy increased apoptosis and decreased mitosis in colon cancer. In this experiment we used HT-29 colon cancer cells to induce subcutaneous cancers in nude mice and a...

Insulin-like growth factors (IGFs) are important for the proliferation of cancer cells. One of their binding proteins, known as insulin-like growth factor binding protein -4 (IGFBP-4) is well known for its inhibitory action on IGFs in vitro. We assessed the effect of IGFBP-4 in prevention of development of colon cancer in vivo. Nude mice were subcu...

Insulin like growth factor-I (IGF-I) is expressed as two isoforms in the heart, a major (IGF-IEa) and minor isoform (IGF-IEb), also known as mechano-growth factor (MGF). These isoforms differ in their E-domain region and their expression dynamics during acute myocardial infarction (MGF, sham=0.43±0.14 vs. MI-2.2±0.4*, IGF-IEa, sham=41±1.0 vs. MI=31...

Little is known about the expression of skeletal muscle-specific isoforms of the insulin-like growth factor-I (IGF-I) gene in response to exercise in humans. Data for women are sparse and the influences of age and physical training status are unknown. Here we aimed to describe the expression of mRNA for the IGF-I isoforms in the quadriceps muscles...

Insulin-like growth factor binding protein-4 (IGFBP-4) is an important member of the insulin-like growth factor (IGF) system. The IGFBP-4 has three domains of which the N-terminal sequence is important for the binding of IGF. It acts as a transport protein for IGF-I and IGF-II and modulates their biological effects. There is increasing evidence tha...

The aim of this review is to clarify the involvement of the insulin-like growth factor (IGF) system in the development of colorectal malignancy. Medline searches were used to identify key articles relating the IGF system with the development of colorectal cancer. The IGF system has been linked to colorectal malignancy by a convergence of data from...

The characterisation of a local tissue repair factor (mechano growth factor, MGF) that is produced by exercised and/or damaged muscle by differential splicing of the IGF-I gene provides understanding of how muscle is maintained in the young normal individual. Mechano growth factor, or MGF, is different to the systemic IGF-I as it has an insert of 4...

Myofibrillar ATPase activity was measured in the epaxial musculature of rainbow trout acclimated to 5 and 21.°C, and goldfish acclimated to 5 and 30°C. The acclimated goldfish showed considerable differences in the specific activity and thermostability of this enzyme. However, such alterations were not apparent in the acclimated trout. The evolutio...

Protein synthesis rates of both red and white muscle were measured using a constant infusion technique in fed and starved rainbow trout over a period of 2 months. In both tissues, rates of protein synthesis fell during starvation although the fall was more rapid in white than in red muscle. The reduced rates of protein synthesis were correlated to...

Groups of common carp were acclimated to either 10°C or 28°C for 6 weeks. Fish were then exercised at 10°C or 20°C, and the critical swimming speed (fatigue velocity) was measured. At 10°C, cold-acclimated carp were capable of significantly higher swimming speeds. When exercised at 20°C. however, the situation was reversed, and warm-acclimated carp...

Myofibrillar ATPase activity was measured in the epaxial musculature of five freshwater species of fish acclimated to extremes of temperature within their tolerance ranges. Changes in the enzyme activity were apparent in carp, tench and roach, cold acclimated fish (10°C) having higher enzyme activity levels than hot acclimated fish (28°C). Such cha...

The composition of the lateral muscles of first-year roach was studied using histological techniques. It was found that all samples had significantly higher levels of red muscles in the hindermost regions, and these levels rose as the fish became larger. Fish from a running water habitat contained significantly more red muscle than fish of the same...

First year roach from a Stillwater habitat were maintained in an’artificial stream for periods of up to 40 days and samples of the lateral musculature were subjected to histological examination. It was found that there was a highly significant increase in the percentage of red muscle present in the hindermost regions of the fish confined for 30 day...

Batches of roach from two contrasting habitats were exercised in a flume at various water velocities for 1 h, and muscle metabolite levels were determined. It was found that the percentage change in lactate was greater in fish from the still water habitat than that in their running water counterparts, and it is proposed that natural conditioning of...

Preliminary experiments were performed to determine the diurnal variation in cortisol, using trout which had been cannulated three days previously. These results indicated that cortisol levels were reasonably stable between 10.00 and 18.00 hours, thus permitting experimentation during this period without diurnal fluctuations masking the cortisol re...

Groups of 6-7 cm length rainbow trout, Salmo gairdneri Richardson, were simultaneously trained at four water velocities (0, 1·4, 2·2 and 3·5 Ls-1) for a period of 46 days. Oxygen consumption and swimming ability (fatigue time) were then measured. Only training at 3·5 Ls-1 increased the swimming ability of the fish. A study of the relative proportio...

The aim of this EU ORCIS project was to optimise the rearing conditions of larval and juvenile sea bass (Dicentrarchus labrax) such that the incidence of lordosis was significantly reduced and coordinated musculo-skeletal growth was improved. This was achieved through an integrated, multidisciplinary approach where an understanding of the underlyin...

Mechano growth factor can produce rapid increases in muscle and strength, giving it considerable therapeutic and doping potential The sequencing of the human genome showed that there are only about 40 000 genes. However, there are many more proteins. This is because some genes are spliced to produce different protein/peptides which usually have di...

The ischemic stroke is the third leading cause of death in developed countries. The C-terminal peptide of mechano-growth factor (MGF), an alternatively spliced variant of insulin-like growth factor 1 (IGF-1), was found to function independently from the rest of the molecule and showed a neuroprotective effect in vivo and in vitro. In vivo, in a ger...

Anderson-Fabry disease is an X-linked lysosomal storage disorder (LSD) caused by α-galactosidase A (AGA) deficiency. There is evidence that LSDs could be corrected by gene transfer, expression and enzyme secretion from a subset of cells or a specific tissue. Such gene therapy has several advantages over an alternative enzyme replacement approach, a...

An aminopeptidase was purified from bovine skeletal muscle by ammonium sulfate fractionation and by successive chromatographies of DEAE-cellulose, Sehacryl S-200, phenyl-sepharose CL-4B, hydroxyapatite and Hi-Trap chelating HP columns. The aminopeptidase was purified about 14-fold over the crude extract with a yield of 1.0% activity. The molecular...

Combining physiological and molecular biology methods made it possible to identify and characterize a local muscle growth/repair factor (MGF). Following resistance exercise, MGF "kick starts" muscle hypertrophy and is important in local tissue repair. Loss of muscle mass in old age and certain diseases is associated with an impaired ability to expr...

Studies in animals and human muscle have demonstrated differential splicing of the insulin-like growth factor-1 gene in response to mechanical strain and damage. We conducted a study on the expression of insulin-like growth factor-1 splice variants in the levator ani muscle after the first vaginal delivery. Ten women were recruited after the first...

In striated muscle, the structural genes associated with muscle fiber phenotype determination as well as muscle mass accretion are regulated largely by mechanical stimuli. Passive stretch of skeletal muscle stimulates muscle growth/hypertrophy and an increased expression of slow muscle genes. We previously identified Ankyrin repeat-domain protein (...

It has been shown that the insulin-like growth factor (IGF-I) gene is spliced in response to mechanical signals producing forms of IGF-I which have different actions. In order to study how mechanical signals influence this gene splicing in developing muscle, C2C12 cells were grown in three-dimensional (3D) culture and subjected to different regimen...

Loss of muscle mass (sarcopenia) is one of the main problems associated with ageing as it has major health care as well as socioeconomic implications. The growth hormone (GH)/IGF-I axis is regarded as an important regulator of muscle mass. However, it is now appreciated that other tissues in addition to the liver express IGF-I and that there are lo...

ATP is an important extracellular signaling molecule mediating its effects by activation of P2X and P2Y receptors. P2 receptors are expressed during muscle development, and recent findings demonstrate that ATP can regulate myoblast proliferation and differentiation in vitro. However, the role of purinergic signaling during regeneration of injured s...

A plasmid containing human coagulation factor VII (hFVII) complementary DNA regulated by a cytomegalovirus promoter was microinjected into fertilized eggs of zebrafish, African catfish, and tilapia. The active form of hFVll was detected in the fish embryos by various assays. This positive expression of human therapeutic protein in fish embryos demo...

• Skeletal muscle is a major source of circulating insulin growth factor-1 (IGF-1), particularly during exercise. It expresses two main isoforms. One of the muscle IGF-1 isoforms (muscle L.IGF-1) is similar to the main liver IGF-1 and presumably has an endocrine action. The other muscle isoform as a result of alternative splicing has a different 3′...

Summary Hypoalbuminaemia and thrombocytopaenia are two clinical problems frequently encountered in patients with chronic liver failure or cancer following treatment with chemotherapy. The current study was designed to assess the magnitude and duration of thrombopoietin and albumin transgene expression hoping to increase the production of albumin an...

Mechano Growth Factor (MGF) is derived from the insulin-like growth factor (IGF-I) but its sequence differs from the systemic IGF-I produced by the liver. MGF is expressed by mechanically overloaded muscle and is involved in tissue repair and adaptation. It is expressed as a pulse following muscle damage and involved in the activation of muscle sat...

Loss of muscle mass and function (sarcopenia) is one of the most marked problems associated with aging because it has major healthcare as well as socioeconomic implications. The growth hormone/IGF-I axis is regarded as an important regulator of muscle mass. However, it is now appreciated that other tissues in addition to the liver express IGF-I. Al...

We compared the neuroprotective effects of a liver-type isoform of insulin-like growth factor-I (IGF-IEa) and its splice variant, mechano-growth factor (MGF), isolated from active skeletal muscle. cDNAs of these peptides were injected into the facial muscle of adult rats prior to facial nerve avulsion. This resulted in significant neuroprotection o...

Thermal cycling is used as a diagnostic test for electronic equipment. It is particularly severe on solder joints that are under both compressive and tensile strain during a cycle as a result of differential thermal expansion. The electronics industry document IPC-SM-785 addresses this problem and provides means whereby joint failure can be predict...

We examined the effects of two levels of gestational undernutrition (50 % and 40 % of ad libitum) on postnatal growth rate, skeletal muscle cellularity and the expression of genes that control muscle growth, in the offspring at weaning. The results showed that the rat pups born to mothers fed the 50 % diet during gestation and a control diet during...

The expression of two isoforms of insulin-like growth factor-I (IGF-I): mechano growth factor (MGF) and IGF-IEa were studied in muscle in response to growth hormone (GH) administration with and without resistance training in healthy elderly men. A third isoform, IGF-IEb was also investigated in response to resistance training only. The subjects (ag...

This chapter describes the expression and role of the different insulin-like growth factor (IGF)-I splice variants in other tissues. The chapter focuses on skeletal muscle and shows that the muscle growth factors (MGF) splice variant that was cloned from mechanically challenged skeletal muscle may be regarded as a local tissue repair factor as well...

The horse is one of the few animals kept and bred for its athletic performance and is therefore an interesting model for human sports performance. The regulation of the development of equine locomotion in the first year of life, and the influence of early training on later performance, are largely unknown. The major structural protein in skeletal m...

In post-mitotic tissues, damaged cells are not replaced by new cells and hence effective local tissue repair mechanisms are required. In skeletal muscle, which is a syncytium, additional nuclei are obtained from muscle satellite (stem) cells that multiply and then fuse with the damaged fibres. Although insulin-like growth factor-I (IGF-l) had been...

The original article to which this Erratum refers was published in Cell Motility and the Cytoskeleton (2003) 54(3) 226–236

Muscle has the ability to take up and express engineered genes and, because it is a post-mitotic tissue, their half-life of expression is prolonged. Although muscle is not regarded as a secretory tissue, in many cases, the gene products enter the systemic circulation. The possibility exists, therefore, of using this approach to alter levels of endo...

Muscle satellite cells are mononuclear cells that remain in a quiescent state until activated when they proliferate and fuse with muscle fibres to donate nuclei, a process necessary for post-embryonic growth, hypertrophy and tissue repair in this post-mitotic tissue. These processes have been associated with expression of the insulin-like growth fa...

Journal of Physiology547, 247–254 (2003)

An understanding of the mechanical and mechano-molecular responses that occur during the differentiation of mouse C2C12 [corrected] myoblasts in 3-D culture is critical for understanding growth, which is important for progress towards producing a tissue-engineered muscle construct. We have established the main differences in force generation betwee...

Using the model of facial nerve avulsion, we have compared the effects of injury, age and diet on motoneuronal survival. One to four weeks after nerve avulsion, 50-75% motoneuron loss was quantified in ad libitum-fed rats aged 7 days (neonate), 6 months (adult) and 24 months (aging) at the time of injury. Evidence of apoptosis was found for neonata...

The mRNA expression of two splice variants of the insulin-like growth factor-I (IGF-I) gene, IGF-IEa and mechano growth factor (MGF), were studied in human skeletal muscle. Subjects (eight young, aged 25-36 years, and seven elderly, aged 70-82 years) completed 10 sets of six repetitions of single legged knee extensor exercise at 80 % of their one r...

Muscle has an intrinsic ability to adapt to different types of work by changing fibre type and muscle mass. This process involves quantitative and qualitative changes in gene expression including those of the myosin heavy chain (MyHC) isogenes that encode different types of molecular motors. Increased expression of slow MyHC and of metabolic genes...

Mechanical conditioning of many tissue engineered construct will be critical, particularly mechano-responsive tissues such as skeletal muscle. It has been shown that application of defined uniaxial loads to 3D constructs through the tensioning- culture force monitor (t-CFM), has been shown to regulate protease expression in fibroblasts (Prajapati e...

In studying the way the musculoskeletal system adapts, it is important to consider how the different tissues interact with each other. During growth, and in response to changes in posture, the functional length of muscle is adjusted by altering the number of sarcomeres in series to the optimum for force generation and power output. In some cases, i...

The physiological function of a recently cloned splice variant of insulin-like growth factor-I (IGF-I; mechano growth factor (MGF)) was studied using an in vitro cell model. Unlike mature IGF-I, the distinct E domain of MGF inhibits terminal differentiation whilst increasing myoblast proliferation. Blocking the IGF-I receptor with a specific antibo...

Muscle has an intrinsic ability to change its mass and phenotype in response to activity. This process involves quantitative and qualitative changes in gene expression, including that of the myosin heavy chain isogenes that encode different types of molecular motors. This, and the differential expression of metabolic genes, results in altered fatig...

Somatic gene therapy for haemophilia has reached the stage when the first phase one safety finding trials are already under way. This information can give rise to misunderstandings about the nature of the trials and the expected outcomes for patients and parents of children with haemophilia who are constantly seeking safer, less invasive and easier...

The RNA-protein interactions of the myosin heavy chain (MyHC) 3' untranslated regions (3'UTRs) were investigated using gel mobility shift assays. Marine skeletal myosin heavy chain mRNAs were amplified using reverse transcription coupled with the polymerase chain reaction (RT-PCR). Four cloned MyHC sequences were identified as slow type 1, fast 2a,...

Sarcopenia is the loss of muscle mass associated with the aging process. Although systemic or circulating growth hormone and insulin-like growth factor-1 levels fall as we age, this is likely to be of lesser importance in regard to muscle mass than the role of locally produced insulin-like growth factor-1s generated in the muscle in response to exe...

For some time, it has been appreciated that muscle mass is regulated locally as well as systemically. We have cloned the cDNA of two isoforms of IGF-1, which are derived from the IGF-1 gene by alternate splicing. The expression of one of these was only detectable after mechanical stimulation. For this reason, this has been called mechano growth fac...

Muscle is the most abundant tissue and myosin is the most abundant protein in this tissue. It is also the protein that generates the force for contraction and exists in different isoforms. The myosin heavy chains (hc) represent a range of different molecular motors which are encoded in a family of different genes. These endow different contractile...

Muscle provides several striking examples of the way a tissue can adapt to different types of physical signals. Adaptation to a different work regime is brought about by changes in fiber type and cross-sectional area, which result in altered fatigue resistance and power output. This process involves quantitative and qualitative changes in gene expr...

The effect of different temperatures (4 degrees C and 12 degrees C) on myogenic regulatory factors (MyoD and myogenin) and myosin heavy chain (MyHC) expression was investigated in rainbow trout (Onchrhynchus mykiss) during early development. MyoD is first switched on at stage 14 [about 5 somites are formed (1/2 epiboly)] while myogenin mRNA is expr...

We have investigated if the administration of plasmid vectors engineered for gene delivery into mammalian muscle induced the production of anti-double stranded (ds) DNA and anti-nuclear autoantibodies in normal and autoimmunity-prone mouse models. In normal mice, repeated injection of plasmid DNA did not trigger an anti-DNA response. The presence o...

The response of insulin-like growth factor-1 (IGF-1) signalling and the capacity of skeletal muscle to adapt to mechanical overload was studied using synergistic muscle ablation. Overload of the plantaris and soleus resulted in marked hypertrophy and activation of satellite cells (as indicated by MyoD expression), particularly in young rats. Two mu...