A functional IGF‐I receptor is not necessary for in vivo skeletal muscle hypertrophy

Insulin-like growth factor-I (IGF-I) is an important autocrine/paracrine mediator of skeletal-muscle growth and development. To develop a definitive cultured cell model of skeletal-muscle hypertrophy, C2C12 cells were stably transfected with IGF-I and clonal lines developed and evaluated. Quantitative morphometric analysis showed that IGF-I-transfected myotubes had a larger area (2381±60 µm2 versus 1429±39 µm2; P< 0.0001) and a greater maximum width (21.4±0.6 µm versus 13.9±0.3 µm; P< 0.0001) than control C2C12 myotubes, independent of the number of cell nuclei per myotube. IGF-I-transfected myotubes had higher levels of protein synthesis but no difference in DNA synthesis when compared with control myotubes, indicating the development of hypertrophy rather than hyperplasia. Both lactate dehydrogenase and alanine aminotransferase activities were increased (3- and 5-fold respectively), and total lactate levels were higher (2.3-fold) in IGF-I-transfected compared with control myotubes, indicating an increase in anaerobic glycolysis in the hypertrophied myotubes. However, expression of genes involved in skeletal-muscle growth or hypertrophy in vivo, e.g. myocyte nuclear factor and myostatin, was not altered in the IGF-I myotubes. Finally, myotube hypertrophy could also be induced by treatment of C2C12 cells with recombinant IGF-I or by growing C2C12 cells in conditioned media from IGF-I-transfected cells. This quantitative model should be uniquely useful for elucidating the molecular mechanisms of skeletal-muscle hypertrophy.

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Cellular mechanisms regulating protein synthesis and skeletal muscle hypertrophy in animals

Journal of Applied Physiology ◽

10.1152/japplphysiol.91355.2008 ◽

2009 ◽

Vol 106 (4) ◽

pp. 1367-1373 ◽

Cited By ~ 110

Author(s):

Mitsunori Miyazaki ◽

Karyn A. Esser

Keyword(s):

Skeletal Muscle ◽

Cell Culture ◽

Protein Synthesis ◽

Mechanical Loading ◽

Muscle Hypertrophy ◽

Mammalian Target Of Rapamycin ◽

Cellular Mechanisms ◽

Skeletal Muscle Hypertrophy

Growth and maintenance of skeletal muscle mass is critical for long-term health and quality of life. Skeletal muscle is a highly adaptable tissue with well-known sensitivities to environmental cues such as growth factors, cytokines, nutrients, and mechanical loading. All of these factors act at the level of the cell and signal through pathways that lead to changes in phenotype through multiple mechanisms. In this review, we discuss the animal and cell culture models used and the signaling mechanisms identified in understanding regulation of protein synthesis in response to mechanical loading/resistance exercise. Particular emphasis has been placed on 1) alterations in mechanical loading and regulation of protein synthesis in both in vivo animal studies and in vitro cell culture studies and 2) upstream mediators regulating mammalian target of rapamycin signaling and protein synthesis during skeletal muscle hypertrophy.

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Serum IGF-I-Deficiency Does Not Prevent Compensatory Skeletal Muscle Hypertrophy in Resistance Exercise

Experimental Biology and Medicine ◽

10.3181/0808-rm-251 ◽

2009 ◽

Vol 234 (2) ◽

pp. 164-170 ◽

Cited By ~ 41

Author(s):

Wayne Matheny ◽

Edward Merritt ◽

Symeon V. Zannikos ◽

Roger P. Farrar ◽

Martin L. Adamo

Keyword(s):

Skeletal Muscle ◽

Resistance Exercise ◽

Muscle Hypertrophy ◽

Skeletal Muscle Hypertrophy ◽

Igf I

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Localized infusion of IGF-I results in skeletal muscle hypertrophy in rats

Journal of Applied Physiology ◽

10.1152/jappl.1998.84.5.1716 ◽

1998 ◽

Vol 84 (5) ◽

pp. 1716-1722 ◽

Cited By ~ 253

Author(s):

Gregory R. Adams ◽

Samuel A. McCue

Keyword(s):

Skeletal Muscle ◽

Dna Content ◽

Muscle Hypertrophy ◽

Muscle Protein ◽

Weight Bearing ◽

Muscle Size ◽

Heart Weight ◽

Protein Ratio ◽

Skeletal Muscle Hypertrophy ◽

Igf I

Insulin-like growth factor I (IGF-I) peptide levels have been shown to increase in overloaded skeletal muscles (G. R. Adams and F. Haddad. J. Appl. Physiol. 81: 2509–2516, 1996). In that study, the increase in IGF-I was found to precede measurable increases in muscle protein and was correlated with an increase in muscle DNA content. The present study was undertaken to test the hypothesis that direct IGF-I infusion would result in an increase in muscle DNA as well as in various measurements of muscle size. Either 0.9% saline or nonsystemic doses of IGF-I were infused directly into a non-weight-bearing muscle of rats, the tibialis anterior (TA), via a fenestrated catheter attached to a subcutaneous miniosmotic pump. Saline infusion had no effect on the mass, protein content, or DNA content of TA muscles. Local IGF-I infusion had no effect on body or heart weight. The absolute weight of the infused TA muscles was ∼9% greater ( P < 0.05) than that of the contralateral TA muscles. IGF-I infusion resulted in significant increases in the total protein and DNA content of TA muscles ( P < 0.05). As a result of these coordinated changes, the DNA-to-protein ratio of the hypertrophied TA was similar to that of the contralateral muscles. These results suggest that IGF-I may be acting to directly stimulate processes such as protein synthesis and satellite cell proliferation, which result in skeletal muscle hypertrophy.

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Role of IGF-I in follistatin-induced skeletal muscle hypertrophy

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00098.2015 ◽

2015 ◽

Vol 309 (6) ◽

pp. E557-E567 ◽

Cited By ~ 16

Author(s):

Caroline Barbé ◽

Stéphanie Kalista ◽

Audrey Loumaye ◽

Olli Ritvos ◽

Pascale Lause ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Mass ◽

Skeletal Muscle Mass ◽

Muscle Hypertrophy ◽

Muscle Growth ◽

Skeletal Muscle Hypertrophy ◽

Low Concentrations ◽

Igf I

Follistatin, a physiological inhibitor of myostatin, induces a dramatic increase in skeletal muscle mass, requiring the type 1 IGF-I receptor/Akt/mTOR pathway. The aim of the present study was to investigate the role of IGF-I and insulin, two ligands of the IGF-I receptor, in the follistatin hypertrophic action on skeletal muscle. In a first step, we showed that follistatin increases muscle mass while being associated with a downregulation of muscle IGF-I expression. In addition, follistatin retained its full hypertrophic effect toward muscle in hypophysectomized animals despite very low concentrations of circulating and muscle IGF-I. Furthermore, follistatin did not increase muscle sensitivity to IGF-I in stimulating phosphorylation of Akt but, surprisingly, decreased it once hypertrophy was present. Taken together, these observations indicate that increased muscle IGF-I production or sensitivity does not contribute to the muscle hypertrophy caused by follistatin. Unlike low IGF-I, low insulin, as obtained by streptozotocin injection, attenuated the hypertrophic action of follistatin on skeletal muscle. Moreover, the full anabolic response to follistatin was restored in this condition by insulin but also by IGF-I infusion. Therefore, follistatin-induced muscle hypertrophy requires the activation of the insulin/IGF-I pathway by either insulin or IGF-I. When insulin or IGF-I alone is missing, follistatin retains its full anabolic effect, but when both are deficient, as in streptozotocin-treated animals, follistatin fails to stimulate muscle growth.

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Conditional Activation of Akt in Adult Skeletal Muscle Induces Rapid Hypertrophy

Molecular and Cellular Biology ◽

10.1128/mcb.24.21.9295-9304.2004 ◽

2004 ◽

Vol 24 (21) ◽

pp. 9295-9304 ◽

Cited By ~ 269

Author(s):

Ka-Man V. Lai ◽

Michael Gonzalez ◽

William T. Poueymirou ◽

William O. Kline ◽

Erqian Na ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Hypertrophy ◽

Active Form ◽

Skeletal Muscle Atrophy ◽

Adult Skeletal Muscle ◽

Lean Muscle Mass ◽

Skeletal Muscle Hypertrophy ◽

Novel Method ◽

The Subject

ABSTRACT Skeletal muscle atrophy is a severe morbidity caused by a variety of conditions, including cachexia, cancer, AIDS, prolonged bedrest, and diabetes. One strategy in the treatment of atrophy is to induce the pathways normally leading to skeletal muscle hypertrophy. The pathways that are sufficient to induce hypertrophy in skeletal muscle have been the subject of some controversy. We describe here the use of a novel method to produce a transgenic mouse in which a constitutively active form of Akt can be inducibly expressed in adult skeletal muscle and thereby demonstrate that acute activation of Akt is sufficient to induce rapid and significant skeletal muscle hypertrophy in vivo, accompanied by activation of the downstream Akt/p70S6 kinase protein synthesis pathway. Upon induction of Akt in skeletal muscle, there was also a significant decrease in adipose tissue. These findings suggest that pharmacologic approaches directed toward activating Akt will be useful in inducing skeletal muscle hypertrophy and that an increase in lean muscle mass is sufficient to decrease fat storage.

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