Marta Fiorotto, PhD
Associate Professor of Pediatrics
Baylor College of Medicine
Ph.D. University of Cambridge, U.K.
Postdoctoral Fellowship Baylor College of Medicine
Developmental Determinants of Skeletal Muscle Growth
In mammals, the accretion of skeletal muscle proteins is most rapid during late gestation and in the neonatal period. The growth process during this time is unique because it is driven by both hyperplasia of muscle satellite cells and hypertrophy of the myofibers. Concurrently, the tissue undergoes the terminal steps in its compositional maturation, which results in the attainment of full functional capacity. Subsequently, muscle growth velocity rapidly decelerates and the high growth rates of the immature muscle are never replicated.
The developmental processes specific to the perinatal period represent the central theme of our laboratory's current research. We have two principal objectives: our first goal is to identify those characteristics that confer on the immature muscle its unique capacity for rapid growth. We have established that a primary factor is the ability to sustain high rates of protein synthesis if nutrients are in ample supply. These rates of protein synthesis are enabled by a relatively high abundance of ribosomes, which decreases in parallel to the developmental decline in protein synthesis rates, local muscle insulin-like growth factor concentration, and satellite cell division. Identification of the interrelationships among these processes is one focus of this research objective. A second focus within this research objective is to assess the contribution of transcriptional regulation to translational control during the perinatal stage of muscle development.
Our second major objective is to identify the mechanisms that underlie the varying effects of nutrient intake on the growth of skeletal muscle according to its developmental stage. In the perinatal period, the growth of skeletal muscle is highly dependent on nutrient supply, although we have shown that the maturation of the muscle phenotype, assessed from the expression of myosin isoforms and other developmentally regulated proteins, is relatively unaffected. This surprising resilience in compositional maturation is attributable to adaptations in the turnover of muscle proteins in response to variations in nutrient supply. Thus, the primary consequence of an inadequate nutrient intake during early life is a reduction in the overall accretion of muscle proteins, which consequently will have a negative impact on those aspects of muscle function that are mass-dependent. We and others have established that the ability to recuperate the deficit in muscle mass upon nutritional rehabilitation depends on the developmental age when this occurs. If refeeding does not occur before the muscle has attained functional maturity-- that is, before weaning -- muscle mass is permanently compromised. We are embarking on studies to determine the mechanisms that limit the age when "catch-up" growth can occur, and to evaluate the efficacy of various interventions in reversing these muscle deficits.
Insofar as the growth rate of a tissue is the net product of a variety of coordinated biological processes acting on that tissue, the regulation of muscle growth in the immature organism must be studied at the whole-animal level. Our approach is to use various dietary, surgical, endocrine, and transgenic manipulations to perturb growth at key stages of skeletal muscle development. In these experimental models, we combine measurements of protein turnover, using in vivo kinetic analysis of molecular tracers, with a variety of molecular and cell biology techniques to identify the mechanisms responsible for the observed responses in cell and tissue growth. Integration of these observations enables us to more accurately assess the impact of developmental age on the relative significance of biological processes that are taking place concurrently in the muscle.
Hadsell DL, Torres DT, Lawrence NA, George J, Parlow AF, Lee AV, Fiorotto ML. Overexpression of des(1-3) insulin-like growth factor 1 in the mammary glands of transgenic mice delays the loss of milk production with prolonged lactation. Biol Reprod. 2005 Dec;73(6):1116-25. Epub 2005 Aug 3.
Oliver WT, Rosenberger J, Lopez R, Gomez A, Cummings KK, Fiorotto ML. 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. 146(12):5455-5462, 2005.
Hornberger TA, Stuppard R, Conley KE, Fedele MJ, Fiorotto ML, Chin ER, Esser KA. Mechanical stimuli regulate rapamycin-sensitive signalling by a phosphoinositide 3-kinase-, protein kinase B- and growth factor-independent mechanism. Biochem J. 380(Pt 3):795-804, 2004.
Draghia-Akli R, Fiorotto ML. A new plasmid-mediated approach to supplement somatotropin production in pigs. J Anim Sci. 82 E-Suppl:E264-269, 2004.
Lee AV, Taylor ST, Greenall J, Mills JD, Tonge DW, Zhang P, George J, Fiorotto ML, Hadsell DL. Rapid induction of IGF-IR signaling in normal and tumor tissue following intravenous injection of IGF-I in mice. Horm Metab Res. 35(11-12):651-655, 2003.
Khan AS, Fiorotto ML, Cummings KK, Pope MA, Brown PA, Draghia-Akli R. Maternal GHRH plasmid administration changes pituitary cell lineage and improves progeny growth of pigs. Am J Physiol Endocrinol Metab. 285(1):E224-E231, 2003.
Draghia-Akli R, Ellis KM, Hill LA, Malone PB, Fiorotto ML. High-efficiency growth hormone-releasing hormone plasmid vector administration into skeletal muscle mediated by electroporation in pigs. FASEB J. 17(3):526-528, 2003.
Fiorotto ML, Schwartz RJ, Delaughter MC. Persistent IGF-I overexpression in skeletal muscle transiently enhances DNA accretion and growth. FASEB J. 17(1):59-60, 2003.
Davis TA, Burrin DG, Fiorotto ML. Peter J. Reeds (February 22, 1945-August 13, 2002). J Nutr. 133(1):5-8, 2003.
Fiorotto ML, Schwartz RJ, Delaughter CM. Persistent overexpression of insulin-like growth factor-I in skeletal muscle enhances dna accretion and growth transiently. FASEB J (In Press), 2002
Chakravarthy MV, Fiorotto ML, Schwartz RJ and Booth FW. Long-term IGF-I expression in skeletal muscles attenuates the enhanced in vitro proliferation ability of the resident satellite cells in transgenic mice. Mech Ageing Dev 122: 1303-1320, 2001.
Fiorotto ML, Davis TA, Reeds PJ and Burrin DG. Nonnutritive factors in colostrum enhance myofibrillar protein synthesis in the newborn Pig. Pediatr Res 48: 511-517, 2000.
Fiorotto ML, Davis TA and Reeds PJ. Regulation of myofibrillar protein turnover during maturation in normal and undernourished rat pups. Am J Physiol Regul Integr Comp Physiol 278: R845-R854, 2000.
Lorenzen CL, Koohmaraie M, Shackelford SD, Jahoor F, Freetly HC, Wheeler TL, Savell JW and Fiorotto ML. Protein kinetics in callipyge lambs. J Anim Sci 78: 78-87, 2000.
Criswell DS, Booth FW, DeMayo F, Schwartz RJ, Gordon SE and Fiorotto ML. Overexpression of IGF-I in skeletal muscle of transgenic mice does not prevent unloading-induced atrophy. Am J Physiol 275: E373-E379, 1998.
Fiorotto ML and Davis TA. Food intake alters muscle protein gain with little effect on Na(+)-K(+)-ATPase and myosin isoforms in suckled rats. Am J Physiol 272: R1461-R1471, 1997.
Fiorotto ML, Davis TA, Schoknecht P, Mersmann HJ and Pond WG. Both maternal over- and undernutrition during gestation increase the adiposity of young adult progeny in rats. Obes Res 3: 131-141, 1995.
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