HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text (PDF) All Versions of this Article: 17/1/59 02-0189fjev1    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by FIOROTTO, M. L. Articles by DELAUGHTER, M. C. Search for Related Content PubMed PubMed Citation Articles by FIOROTTO, M. L. Articles by DELAUGHTER, M. C.

Persistent IGF-I overexpression in skeletal muscle transiently enhances DNA accretion and growth ¹

USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, and
^* Department of Molecular and Cell Biology, Baylor College of Medicine, Houston, Texas, USA

²Correspondence: Children’s Nutrition Research Center, 1100 Bates St., Houston, TX 77030, USA. E-mail: martaf{at}bcm.tmc.edu

SPECIFIC AIMS

The primary aim of our study was to identify the anabolic mechanisms that drive IGF-I-induced skeletal muscle hypertrophy by a careful evaluation of the growth response of muscle in transgenic mice (SIS2) in which sustained high levels of expression of human IGF-I in skeletal muscle were attained through the use of the chick skeletal -actin promoter.

Second, we wished to determine the factors responsible for the differences observed in the magnitude of the response of individual muscles and in the pattern of weight gain of male and female transgenic animals.

PRINCIPAL FINDINGS

1. Increased muscle mass accretion in SIS2 mice persisted to 10 wk of age despite continued hIGF-I expression. Hypertrophy was confined to muscles that express type IIB myosin heavy chain.
   
2. For the gastrocnemius, a responsive muscle, total DNA and RNA contents were greater in SIS2 than nontransgenic littermates, and the differences were maximal by 5 wk of age, the youngest age evaluated (Fig. 1 ).
   
3. Enhanced muscle protein accretion in SIS2 mice persisted until 10 wk of age and this difference was sustained until 32 wk of age (Fig. 1) .
   
4. At 5 wk of age, the protein:DNA ratio, an index of myonuclear domain size, was smaller in SIS2 than in nontransgenic littermates, but attained equivalent values by 10 wk. This value was maintained for the duration of the study (Fig. 1) .
   
5. There was no difference in body weight gain between SIS2 and nontransgenic male littermates until 32 wk of age, whereas by 10 wk of age female SIS2 mice were heavier than nontransgenic littermates. This gender-related difference was attributable to a decrease in fat accumulation in SIS2 males relative to nontransgenic littermates, but not in SIS2 females. Total weight of the visceral organs and skin was greater in SIS2 females. There were no gender differences in the accretion of fat-free carcass mass, i.e., combined total muscle and skeleton mass (Fig. 2 ).
   

View larger version (29K): [in this window] [in a new window]   Figure 1. Total protein, DNA, and RNA of gastrocnemius muscles from SIS2 transgenic mice and wild-type (Wdt) control littermates at 5, 10, 20, and 32 wk of age. Top panel: absolute amounts of protein, RNA, and DNA in male and female mice. Values were higher in SIS2 mice (P<0.001) and greater in males than females (P<0.001). Lower panel: the protein/DNA ratio is a measure of myonuclear domain size, and total RNA/DNA and RNA/protein are indicative of ribosomal abundance and protein synthetic capacity, respectively. There was no effect of gender. Protein/DNA was significantly lower in SIS2 mice at 5 wk of age (P<0.001); there were no differences in RNA/DNA; RNA/protein tended to be higher in 5-wk-old SIS2 mice (P<0.07). Values are means ±1 SE (SIS2, n = 13–16 per data point; Wdt, n = 7–8 per data point.

View larger version (31K): [in this window] [in a new window]   Figure 2. Body composition of SIS2 transgenic and Wdt control littermates at 5, 10, 20, and 32 wk of age. Top panel: total body weight, fat, and fat-free masses in male and female mice. The effect of genotype varied according to age and gender (genotype x age x gender, P<0.06). Bottom panel: components of the fat-free mass. Carcass (skeletal musculature and skeleton) was significantly higher in SIS2 mice (P<0.002). The viscera/skin component (includes all internal organs, skin, the head, tail, and paws) was greater in SIS2 mice than in controls (P<0.01); the difference was greater for females (genotype x gender, P<0.05). Values are means ± 1 SE (SIS2, n=13–16 per data point; Wdt, n=7–8 per data point).

CONCLUSION AND SIGNIFICANCE

These observations support those findings that ascribe the primary anabolic effect of local IGF-I on muscle to the stimulation of satellite cell replication. Accretion of protein lagged behind the increase in DNA accretion. The link between the two processes remains to be resolved even though the results, supported by data from previous studies, suggest a link through stimulation of ribosome accretion (Fig. 3 ). We also demonstrated a limited capacity of skeletal muscle to respond to persistent exposure to elevated levels of IGF-I, which might be explained by the down-regulation of the signaling pathways through which IGF-I regulates cell cycle activity. We concluded that under nonstressed conditions, IGF-I stimulates muscle growth by accelerating the progression of cell division.

View larger version (37K): [in this window] [in a new window]   Figure 3. Skeletal muscle growth in SIS2 mice was responsive to IGF-I stimulation for only a limited time. The inevitable increase in the animal’s energetic needs incurred by the greater muscle growth were accommodated in a gender-specific manner. In mature muscle, the enhanced cell division in response to IGF-I was no longer sustained and enhanced muscle growth was blunted. The arrows reflect the direction of change in SIS2 mice relative to the level in wild-type littermates. Deleted symbols in mature muscle represent the loss of response observed in the immature muscle.

The study revealed that, despite the localized expression of IGF in skeletal muscle, effects were not confined to this tissue. There were distal effects on the growth of other tissues and on body composition of the animals as a whole. There were no differences between genotypes in circulating IGF-I concentrations or contemporaneous growth of those muscles that did not express the transgene. Thus, it is probable that this response is linked only secondarily to the IGF-I overexpression and resulted from the influence of the changes in muscle mass on regulation of the organism’s overall energy metabolism, an effect further modulated by the gender of the animal (Fig. 3) .

Given the importance of skeletal muscle for sustaining a good quality of life, much ongoing research is directed toward development of growth hormone/IGF-I-based therapies as a means of regulating muscle mass. Our findings underscore the importance of taking an integrative approach in evaluating the effectiveness of potential therapies, because outcomes may not always be predictable or desirable.

FOOTNOTES

¹ To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.02-0289fje; to cite this article, use FASEB J. (November 15, 2002) 10.1096/fj.02-0289fje

This article has been cited by other articles:

				W. T. Oliver, J. Rosenberger, R. Lopez, A. Gomez, K. K. Cummings, and M. L. Fiorotto The Local Expression and Abundance of Insulin-Like Growth Factor (IGF) Binding Proteins in Skeletal Muscle Are Regulated by Age and Gender But Not Local IGF-I in Vivo Endocrinology, December 1, 2005; 146(12): 5455 - 5462. [Abstract] [Full Text] [PDF]

				P. C. Schulze, J. Fang, K. A. Kassik, J. Gannon, M. Cupesi, C. MacGillivray, R. T. Lee, and N. Rosenthal Transgenic Overexpression of Locally Acting Insulin-Like Growth Factor-1 Inhibits Ubiquitin-Mediated Muscle Atrophy in Chronic Left-Ventricular Dysfunction Circ. Res., September 2, 2005; 97(5): 418 - 426. [Abstract] [Full Text] [PDF]

				M. C. Kostek, M. J. Delmonico, J. B. Reichel, S. M. Roth, L. Douglass, R. E. Ferrell, and B. F. Hurley Muscle strength response to strength training is influenced by insulin-like growth factor 1 genotype in older adults J Appl Physiol, June 1, 2005; 98(6): 2147 - 2154. [Abstract] [Full Text] [PDF]

				V. Sartorelli and M. Fulco Molecular and Cellular Determinants of Skeletal Muscle Atrophy and Hypertrophy Sci. Signal., August 3, 2004; 2004(244): re11 - re11. [Abstract] [Full Text] [PDF]

				T. Shavlakadze, M. Davies, J. D. White, and M. D. Grounds Early Regeneration of Whole Skeletal Muscle Grafts Is Unaffected by Overexpression of IGF-1 in MLC/mIGF-1 Transgenic Mice J. Histochem. Cytochem., July 1, 2004; 52(7): 873 - 883. [Abstract] [Full Text] [PDF]

				J. R. McMullen, T. Shioi, W.-Y. Huang, L. Zhang, O. Tarnavski, E. Bisping, M. Schinke, S. Kong, M. C. Sherwood, J. Brown, et al. The Insulin-like Growth Factor 1 Receptor Induces Physiological Heart Growth via the Phosphoinositide 3-Kinase(p110{alpha}) Pathway J. Biol. Chem., February 6, 2004; 279(6): 4782 - 4793. [Abstract] [Full Text] [PDF]

				F. Haddad, R. R. Roy, H. Zhong, V. R. Edgerton, and K. M. Baldwin Atrophy responses to muscle inactivity. I. Cellular markers of protein deficits J Appl Physiol, August 1, 2003; 95(2): 781 - 790. [Abstract] [Full Text] [PDF]

This Article Full Text (PDF) All Versions of this Article: 17/1/59 02-0189fjev1    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by FIOROTTO, M. L. Articles by DELAUGHTER, M. C. Search for Related Content PubMed PubMed Citation Articles by FIOROTTO, M. L. Articles by DELAUGHTER, M. C.