Overexpression of interleukin-15 induces skeletal muscle hypertrophy in vitro: implications for treatment of muscle wasting disorders.
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 alpha-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.
Quinn
LeBris S
LS
Division of Gerontology and Geriatric Medicine, University of Washington, Seattle 98195, USA. quinnl@u.washington.edu
Anderson
Barbara G
BG
Drivdahl
Rolf H
RH
Alvarez
Belén
B
Argilés
Josep M
JM
D000199:Actins / Q000032:analysis; D000818:Animals; D002100:Cachexia / Q000188:drug therapy; D002460:Cell Line; D002478:Cells, Cultured; D018920:Coculture Techniques; D004247:DNA / Q000032:analysis; D005822:Genetic Vectors; D006984:Hypertrophy; D019409:Interleukin-15 / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D018482:Muscle, Skeletal / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D009135:Muscular Diseases / Q000188:drug therapy; D018995:Myosin Heavy Chains / Q000032:analysis; D012190:Retroviridae / Q000235:genetics; D012518:Sarcomeres / Q000737:chemistry; D013002:Somatomedins / Q000378:metabolism; D014161:Transduction, Genetic
D000199:Actins; D019409:Interleukin-15; D013002:Somatomedins; D004247:DNA; D018995:Myosin Heavy Chains