Elsevier

Experimental Cell Research

Volume 280, Issue 1, 15 October 2002, Pages 55-63
Experimental Cell Research

Regular Article
Overexpression of Interleukin-15 Induces Skeletal Muscle Hypertrophy in Vitro: Implications for Treatment of Muscle Wasting Disorders

https://doi.org/10.1006/excr.2002.5624Get rights and content

Abstract

Interleukin-15 (IL-15) is a novel anabolic factor for skeletal muscle which inhibits muscle wasting associated with cancer (cachexia) in a rat model. To develop a cell culture system in which the mechanism of the anabolic action of IL-15 on skeletal muscle could be examined, the mouse C2 skeletal myogenic cell line was transduced with a retroviral expression vector for IL-15 and compared to sister cells transduced with a control vector. Overexpression of IL-15 induced fivefold higher levels of sarcomeric myosin heavy chain and α-actin accumulation in differentiated myotubes. Secreted factors from IL-15-overexpressing myogenic cells, but not from control cells, induced increased myofibrillar protein accumulation in cocultured control myotubes. IL-15 overexpression induced a hypertrophic myotube morphology similar to that described for cultured myotubes which overexpressed the well-characterized anabolic factor insulin-like growth factor-I (IGF-I). However, in contrast to IGF-I, the hypertrophic action of IL-15 on skeletal myogenic cells did not involve stimulation of skeletal myoblast proliferation or differentiation. IL-15 induced myotube hypertrophy at both low and high IGF-I concentrations. Furthermore, in contrast to IGF-I, which stimulated only protein synthesis under these culture conditions, IL-15 both stimulated protein synthesis and inhibited protein degradation in cultured skeletal myotubes. These findings indicate that IL-15 action on skeletal myogenic cells is distinct from that of IGF-I. Due to the ability of IGF-I to stimulate cell division and its association with several forms of cancer, controversy exists concerning the advisability of treating cachexia or age-associated muscle wasting with IGF-I. Administration of IL-15 or modulation of the IL-15 signaling pathway may represent an alternative strategy for maintaining skeletal muscle mass under these conditions.

References (52)

  • S.V. Brooks et al.

    Skeletal muscle weakness in old age: Underlying mechanisms

    Med. Sci. Sports Exercise

    (1994)
  • S.W.J. Lamberts et al.

    The endocrinology of aging

    Science

    (1997)
  • A.L. Friedlander et al.

    One year of insulin-like growth factor I treatment does not affect bone density, body composition, or psychological measures in postmenopausal women

    J. Clin. Endocrinol. Metab.

    (2001)
  • J. Takala et al.

    Increased mortality associated with growth hormone treatment in critically ill adults

    N. Engl. J. Med.

    (1999)
  • S.A. Lieberman et al.

    Anabolic effects of recombinant insulin-like growth factor-I in cachectic patients with the acquired immunodeficiency syndrome

    J. Clin. Endocrinol. Metab.

    (1994)
  • D. Waters et al.

    Recombinant human growth hormone, insulin-like growth factor I, and combination therapy in AIDS-associated wasting

    Ann. Intern. Med.

    (1996)
  • M.A. Papadakis et al.

    Growth hormone replacement in healthy older men improves body composition but not functional ability

    Ann. Intern. Med.

    (1996)
  • A. Grimberg et al.

    Role of insulin-like growth factors and their binding proteins in growth control and carcinogenesis

    J. Cell. Physiol.

    (2000)
  • H. Yu et al.

    Role of the insulin-like growth factor family in cancer development and progression

    J. Natl. Cancer Inst.

    (2000)
  • G.R. Adams et al.

    The relationships among IGF-I, DNA content, and protein accumulation during skeletal muscle hypertrophy

    J. Appl. Physiol.

    (1996)
  • G.R. Adams et al.

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

    J. Appl. Physiol.

    (1998)
  • P.O. Hasselgren et al.

    Muscle cachexia: current concepts of intracellular mechanisms and molecular regulation

    Ann. Surg.

    (2001)
  • R. Roubenoff et al.

    Sarcopenia: current concepts

    J. Gerontol. A Biol. Sci. Med. Sci.

    (2000)
  • K.H. Grabstein et al.

    Cloning of a T cell growth factor that interacts with the beta chain of the interleukin-2 receptor

    Science

    (1994)
  • L.S. Quinn et al.

    Interleukin-15: A novel anabolic cytokine for skeletal muscle

    Endocrinology

    (1995)
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