Impact of placental insufficiency on fetal skeletal muscle growth

Abstract

Intrauterine growth restriction (IUGR) caused by placental insufficiency is one of the most common and complex problems in perinatology, with no known cure. In pregnancies affected by placental insufficiency, a poorly functioning placenta restricts nutrient supply to the fetus and prevents normal fetal growth. Among other significant deficits in organ development, the IUGR fetus characteristically has less lean body and skeletal muscle mass than their appropriately-grown counterparts. Reduced skeletal muscle growth is not fully compensated after birth, as individuals who were born small for gestational age (SGA) from IUGR have persistent reductions in muscle mass and strength into adulthood. The consequences of restricted muscle growth and accelerated postnatal “catch-up” growth in the form of adiposity may contribute to the increased later life risk for visceral adiposity, peripheral insulin resistance, diabetes, and cardiovascular disease in individuals who were formerly IUGR. This review will discuss how an insufficient placenta results in impaired fetal skeletal muscle growth and how lifelong reductions in muscle mass might contribute to increased metabolic disease risk in this vulnerable population.

1. The effects of placental insufficiency on fetal skeletal muscle growth

1.1 Fetal adaptation to increased placental resistance

Placental insufficiency affects ∼8% of all pregnancies and commonly begins early in pregnancy for a multitude of reasons, including maternal chronic disease (chronic hypertension, pregnancy-induced hypertension, and other vascular disorders), placental disorders (preeclampsia, abruption, infarcts), and idiopathic causes (Rozance et al., 2016). Maternal/placental conditions that obliterate small muscular arteries result in increased placental vascular resistance and decreased diastolic flow in the umbilical artery (demonstrated by a high pulsatility index) (Berkley et al., 2012). In response to reduced umbilical blood flow and decreasing fetal oxygenation, the fetal ductus venosus dilates to shunt oxygenated blood from the umbilical vein away from the liver to ensure an adequate supply of oxygen and nutrients to the heart and brain (Tchirikov et al., 2006). The middle cerebral artery also dilates (demonstrated by a low pulsatility index) to maximize blood flow to the brain; providing nutrients and oxygen that spare brain growth restriction relative to overall fetal growth. Doppler velocimetry abnormalities in the umbilical artery are the gold standard for defining placental insufficiency-induced IUGR status (ACOG, 2013). This is opposed to either the population-based term small for gestational age (SGA), which refers to infants born <10% on standard intrauterine growth charts, or low birth weight (LBW) at term gestation, which refers to neonates born with a birthweight of <2500 grams. Most human epidemiological studies to date use these terms to represent IUGR status. However, it should be noted that these terms will include IUGR neonates as well as those normal neonates born constitutionally small.

Redistribution of blood flow to the vital organs such as the brain occurs at the expense of nutrient and oxygen delivery to the periphery (Tchirikov et al., 1998, Yajnik, 2004) (Figure 1). These selective reductions in blood flow and oxygen supply to the peripheral musculature likely contribute to 25-40% reductions in muscle mass observed in IUGR fetuses and neonates when compared to their appropriate for gestational age (AGA) counterparts (Baker et al., 2010, Beltrand et al., 2008, Larciprete et al., 2005, Padoan et al., 2004, Yau et al., 1993). However, even “brain sparing” is incomplete, as head circumference in IUGR infants is frequently below the 10^th percentile for gestational age (Kramer et al., 1989) with reduced brain volume (Toft et al., 1995) and higher risk of poor neurodevelopmental outcome (Arcangeli et al., 2012, De Jesus et al., 2013, Guellec et al., 2015, von Beckerath et al., 2013).

Figure 1. Redistribution of blood flow in IUGR.

Dilation of the ductus venosus and middle cerebral artery shunts oxygen and nutrients from the umbilical vein directly to the heart and brain and away from skeletal muscle (diagram modified from Yainik, 2004).

1.2 Myogenesis

In severe cases of placental insufficiency, onset occurs as early as the second trimester of human pregnancy (De Jesus et al., 2013) with progressive reduction in nutrient and oxygen delivery to the fetus and subsequent development of growth factor deficiencies. Understanding fetal skeletal muscle development (myogenesis) across gestation is important in order to investigate how placental insufficiency and chronic nutrient restriction impact skeletal muscle growth.

Much of what we know about the timing and regulation of myogenesis comes from animal models, notably livestock (sheep, cows) in which the timing of myogenesis is similar to humans (Du et al., 2010, Romero et al., 2013) (Figure 2). The primary (embryonic) stage of muscle fiber formation occurs by the end to end fusion of myogenic precursor cells into primary myotubes and begins at 0.2 of gestation (Wilson et al., 1992). Primary myotubes form the scaffold for subsequent myotube formation. The secondary (fetal) stage of myogenesis involves rapid proliferation of myoblasts that differentiate and fuse to form multinucleated myotubes and secondary myofibers, beginning at 0.2 of gestation and peaking around 0.6 of gestation (Fahey et al., 2005). Based on environmental signals, such as insulin like-growth factors (Ren et al., 2010), myoblasts either proliferate for self-renewal or align to differentiate into myotubes (Yan et al., 2013). Pax transcription factors (Pax3, Pax7) in myogenic precursors regulate the progressive expression of highly conserved myogenic regulatory factors (MRFs), including Myf5 and MyoD, which are considered determination factors, and myogenin (MyoG), which signifies terminal differentiation (Bentzinger et al., 2012).

Figure 2. Schematic representation of fetal myogenesis during pregnancy.

The fraction of gestation when primary (embryonic) and secondary (fetal) stages of myogenesis are based on studies from sheep, cow, and human (Du et al., 2010, Romero et al., 2013, Wilson et al., 1992). Pax transcription factors Pax3 and Pax7 define the progenitor cell population during fetal myogenesis (Wang et al., 2010). Pax7 is expressed in fetal myoblasts, in addition to Myf5 and MyoD which commit cells to the myogenic program. Expression of the terminal differentiation genes, Myf6 (also known as Mrf4) and MyoG, are expressed in myotubes(Bentzinger et al., 2012). Myofibers grow by hypertrophy late in gestation and in postnatal life.

Muscle grows primarily by myofibrillar protein synthesis and hypertrophy of myofibers during the final third of gestation, though this process includes continued proliferation and fusion of myoblasts into established myofibers (McCoard et al., 2001, Stickland, 1981). The postnatal (adult) stage of myogenesis involves maintenance of satellite cells that reside around the muscle fibers in a quiescent state and are activated during muscle growth, regeneration, and repair (Wang et al., 2014, Zammit et al., 2006). The stages of myogenesis are similar among vertebrates, though secondary myogenesis in humans, sheep, and cows occurs earlier in gestation than in rodents (Du et al., 2010) and is more complex with successive generations of myotubes (tertiary) adding to the scaffold (McLennan, 1994, Wilson et al., 1992).

1.3 Impact of placental insufficiency on myoblast proliferation

The concept that chronic fetal undernutrition in utero may disrupt normal myogenesis was introduced over 40 years ago by Elsie Widdowson, a pioneer of child nutrition and growth (Widdowson et al., 1972). Her statements were based on several studies which showed muscle fiber number to be set at birth (Rowe et al., 1969, Stickland et al., 1975, Widdowson et al., 1972, Wigmore et al., 1983). In a variety of species, maternal nutrient restriction during pregnancy limits fetal myoblast cell cycle activity, reduces myonuclei per myofiber, and reduces myofiber number in offspring (Bayol et al., 2004, Costello et al., 2008, Dwyer et al., 1995, Dwyer et al., 1992, Fahey et al., 2005, Greenwood et al., 2000, Greenwood et al., 1999, Osgerby et al., 2002, Prakash et al., 1993, Wilson et al., 1988). Though less well studied, placental insufficiency independent of maternal nutrient intake also results in decreased proliferative capacity of fetal myoblasts, as measured by decreased expression of proliferating cell nuclear antigen (PCNA) and reduced rates of replication in vitro (Yates et al., 2014).

The mechanisms that result in impaired proliferation and formation of myofibers are not known, though reduced availability of important fetal growth factors known to regulate myoblast proliferation, such as insulin and insulin-like growth factors (IGFs) (Fowden, 2003), are likely candidates. Igf1 heterozygous knockouts in mice demonstrate reduced muscle mass (Powell-Braxton et al., 1993), whereas homozygous knockouts have severe muscle hypoplasia from both decreased myocyte number and myofiber cross-sectional area (Liu et al., 1993, Mavalli et al., 2010). Similarly, mutations in the IGF1 and IGF1 receptor genes in humans cause both intrauterine and postnatal growth restriction (Abuzzahab et al., 2003, Woods et al., 1996), as do newly discovered mutations in the IGF2 gene (Begemann et al., 2015). Insulin also functions as a potent skeletal muscle growth factor. The absence of insulin signaling in insulin receptor knock-out mice contributes to reduced muscle mass and function though decreased protein synthesis (O'Neill et al., 2010). Pancreatectomy in fetal sheep results in growth restricted fetuses with decreased upper and lower extremity limb length (Fowden et al., 1989). These data are consistent with lack of insulin as the cause of growth restriction in cases of pancreatic agenesis in humans (Lemons et al., 1979). Interestingly, IGFs have been shown to paradoxically stimulate both myoblast proliferation and differentiation (Florini et al., 1993). The presence of hypoxia might be one of the factors that determine whether IGF1 promotes proliferation over differentiation (Ren et al., 2010). These interactions may be particularly important in the complex physiological milieu of an IUGR fetus, where concentrations of insulin, IGF1, and oxygen are lower than those of normally growing fetuses.

1.4 Impact of placental insufficiency on myofiber hypertrophy

Myofiber hypertrophy, or an increase in fiber diameter and length, occurs as a net increase in protein accretion based on balance between protein synthesis and degradation rates. Late gestation fetal and postnatal muscle growth occurs primarily by myofiber hypertrophy (White et al., 2010). Maternal nutrient restriction in sheep, especially towards the end of gestation, reduces myofiber hypertrophy and muscle weights in the fetus (Fahey et al., 2005), as do models of placental insufficiency in guinea pigs and sheep (Bauer et al., 2003, Yates et al., 2014). The AKT-mTORC1 signaling pathway is one of the primary regulators of muscle protein synthesis in response to anabolic stimuli such as amino acids, insulin, and IGF1 in fetal lambs (Anderson et al., 2005, Brown et al., 2009, Shen et al., 2002) as well as in neonatal piglets (O'Connor et al., 2003, O'Connor et al., 2003, Suryawan et al., 2008, Suryawan et al., 2012). This pathway also has been implicated in reducing fetal muscle protein synthesis under conditions of short term (5 day) maternal fasting in sheep (Shen et al., 2005), and in men who were SGA at birth (Jensen et al., 2008, Ozanne et al., 2005). However, it is not known whether the IUGR fetus slows myofiber hypertrophy via adaptation to reduced nutrients and growth factors, or whether it activates protein breakdown as a result of cellular stress. In fact, AKT is a regulator for both synthesis (4E-BP1, p70S6K) and breakdown pathways (FOXO3) in response to growth factor availability (Bonaldo et al., 2013). Likely, these processes are not mutually exclusive; the fetus might develop a slower growth rate in response to redistribution of blood flow away from the peripheral vasculature (including skeletal muscle) early in the course of placental insufficiency, but then might activate catabolic pathways in the setting of worsening hypoxia and increased catecholamine and cortisol production as placental insufficiency progresses. This is a fundamental area of future investigation, as treatments to improve muscle growth will vary based on whether growth is slowed because of decreased anabolism, or increased catabolism.

1.4 Postnatal growth restriction of muscle in preterm infants

Early life reductions in skeletal muscle growth extend beyond pregnancies affected by placental insufficiency. Extremely preterm infants who were born AGA experience postnatal growth restriction in the Neonatal Intensive Care Unit that includes deficits in muscle mass (Dusick et al., 2003, Ehrenkranz et al., 2006, Johnson et al., 2012). The principal cause of postnatal growth restriction in preterm infants is under-nutrition compared to the nutrition these infants would have received in utero, with contribution of adverse effects of their medical complications (hypoxia, anemia, stress hormone production, and medications that limit protein accretion) (Ehrenkranz, 2010, Ramel et al., 2014). Therefore, preterm birth and its subsequent problems of under-nutrition and unstable physiological conditions can disrupt normal muscle development independent of IUGR, as preterm infants who were not IUGR have decreased lean mass and increased fat mass at the time of discharge (Johnson et al., 2012). Thus, determining the mechanisms responsible for reduced muscle mass in the perinatal and neonatal period has even broader implications, as the rate of preterm birth in the United States remains unacceptably high (Blencowe et al., 2012).

2. Implications of reduced fetal muscle mass

2.1. Persistent reductions in muscle mass and strength

A large number of epidemiological studies have found associations between birthweight and body composition outcomes in later life and are summarized in Table 1. The overwhelming majority of studies show that birthweight, used as an index of the effects of the intrauterine environment on fetal growth, is positively correlated with lean mass and/or fat free mass, and, to a much lesser extent (and even sometimes inversely correlated), with fat mass. The correlation between birthweight and lean mass has been observed in large, diverse populations globally and applies to both males and females. In most studies, the positive correlation between birthweight and lean mass persists after adjusting for body size (weight, height, body mass index) as well as other factors that might influence body composition, such as socioeconomic status, alcohol consumption, and physical activity. Body composition in relation to birthweight has been evaluated during early childhood, prior to the onset of lifestyle factors, as well as during late adulthood, when the programming of body composition tends to amplify (Singhal et al., 2003). Table 1 includes three studies that evaluated both monozygotic (MZ) and dizygotic (DZ) twin pairs to further distinguish effects of the fetal environment from those of the postnatal environment on body composition (Loos et al., 2001, Loos et al., 2002, Skidmore et al., 2009). All three of these twin studies showed a positive correlation between birthweight and lean mass and an inverse relationship between birthweight and measures of body fat percentage (skinfold thickness and muscle to fat ratios). When pair-wise comparisons were made, the heavier twin at birth had more lean mass in adulthood compared to the lighter twin in males (Loos et al., 2001), with less of an effect observed in females (Loos et al., 2002). Both within-pair and between-pair effects were noted in MZ and DZ twins (Skidmore et al., 2009), implicating that both an adverse intrauterine environment as well as postnatal effects impact later life body composition.

Table 1. Studies that associate birthweight to muscle mass and strength later in life.

Author	Place	Age	Measurements	Associations among birthweight, body composition, and muscle strength
Children and Adolescents
(Lapillonne et al., 1997)	France	2d	DXA	SGA (vs. AGA): less LM and FM at the same GA
(Hediger et al., 1998)	U.S.	2-47m	ANTH	SGA (vs. LGA): less lower arm muscle area, % body fat less affected
(Singhal et al., 2003)	U.K.	7-16y	ANTH; BIA, DXA	BW positively correlated with FFM, not FM or BMI; Adjusted for age, sex, puberty, SES, PA
(Murphy et al., 2006)	U.K.	∼6y	ANTH; BIA	BW positively correlated with FFM and FM; Adjusted for BMI
(Joglekar et al., 2007)	India	6-7y	ANTH; DXA	BW positively correlated with FFM and FM; Adjusted for GA, age
(Chomtho et al., 2008)*	U.K.	4-20y	ANTH; DXA, air-plethysmography, 2H-dilution	BW positively correlated with FFM (males), not FM or % fat; Adjusted for Ht, puberty, PA, SES, ethnicity, parental BMI
(Ortega et al., 2009)	Spain	13-18y	ANTH; grip strength	BW positively correlated with Ht, BMI, FFM, fat %, WC, and grip strength (grip strength attributed to FFM)
(Baker et al., 2010)	U.S.	2m - 8y	ANTH	LBW (vs. NBW): less growth of arm muscle area; Adjusted for sex, ethnicity, SES, body size
(Moura-Dos-Santos et al., 2013)	Brazil	7-10y	ANTH; grip strength	LBW (vs. HBW): lower grip strength and running speed; Adjusted for age, sex, Wt, PA, FFM
Young adulthood
(Kahn et al., 2000)	U.S.	17-22y M	ANTH	BW positively correlated with BMI and MTC+bone area, not % body fat
(Loos et al., 2001)‡	Belgiu m	18-34y M twins	ANTH; BIA	BW positively correlated with LM, inversely correlated with % body fat, W-H ratio; Heavier (vs. lighter) twin was taller, less FM, more LM; Adjusted for adult Wt
(Loos et al., 2002)‡	Belgiu m	18-34y F twins	ANTH; BIA	BW positively correlated with LM, inversely correlation with % body fat, W-H ratio; Heavier (vs. lighter) twin was taller; Adjusted for adult Wt
(Sachdev et al., 2005)	India	26-32y	ANTH	BW positively correlated with Ht and LM (both sexes) and BMI and FM (women only); Adjusted for age, education, occupation, alcohol use, smoking, PA, parity, SES
(Brutsaert et al., 2011)	U.S.	∼20y F	Hydro-densitometry; grip strength	Low PI (vs. high PI): lower grip strength, lower max isometric contraction, higher rate of fatigue, and diminished training response; adjusted for FFM
Older adulthood
(Gale et al., 2001)	U.K.	70-75y	Anthropometrics; DXA	BW positively correlated with LM and Ht, inversely correlated with FM; Adjusted for age, sex, Ht, Wt
(Eriksson et al., 2002)	Finland	65-75y	ANTH; BIA	BW, PI, and length at birth positively correlated with FFM
(Sayer et al., 2004)	U.K.	∼64y M	ANTH; grip strength	BW positively correlated with FFM, BMI, MUAC, MTC, and grip strength; not % body fat, W-H ratio, and grip strength; Adjusted for SES, PA, smoking, alcohol use
(Kensara et al., 2005)	U.K.	64-72y M	ANTH; DXA, Air-plethysmography	LBW (vs. HBW): less FFM, less muscle, higher % body fat, lower MTF ratio, and central fat distribution; Adjusted for Wt plus Ht, SES, PA, smoking
(Yliharsila et al., 2007)	Finland	56-70y	ANTH; BIA; grip strength	BW positively correlated with lean mass and grip strength, inversely correlated with % body fat; Adjusted for age/adult Ht, age/adult BMI, mat size, age, smoking, PA, SES
(Skidmore et al., 2009)*†	U.K.	18-80y twins	ANTH; DXA	BW positively correlated with LM, FM, and MTF ratio; Both within-pair and between-pair effects noted; Adjusted for age and BMI
(Patel et al., 2012)	U.K.	68-76y M	ANTH; muscle biopsy; DXA	LBW (vs. HBW): less FFM, higher % body fat, and lower fiber score (myofiber density × leg lean mass); fiber score attenuated when adjusted for age, Ht, PA

Birthweight (BW) obtained from birth records or birth certificates.

^*indicates BW obtained by recall;

^†GA unknown;

^‡GA >35 wks. Both sexes were included unless noted by M, males or F, females only.

Abbreviations: d, days; m, months; y, years; GA, gestational age; M, male; F, female; PI, ponderal index; LBW, low BW; NBW, normal BW; HBW, high BW; SGA, small for GA; AGA, appropriate for GA; LGA, large for GA; WC, waist circumference; W-H, waist to hip; MTF, muscle-to-fat; FFM, fat free mass; FM, fat mass; LM, lean mass; MUAC, midupper arm circumference; MTC, midthigh circumference; HC, hip circumference; SES, socioeconomic status; PA, physical activity; BIA, bioelectrical impedance; DXA, dual-energy X-ray absorptiometry; ANTH, anthropometrics

In some studies, birthweight is used categorically to compare low birth weight (LBW) or SGA neonates (represented as < 2500 grams or <10% on standard intrauterine growth charts at term gestation, respectively) to normal weight neonates, which might better identify specific effects of pathological fetal undergrowth on body composition (Table 1). For example, a study by Baker et al. used data from the Third National Health and Nutrition Examination Survey to demonstrate that while head circumference growth is normal between 2 months and 8 years of age in LBW children born at term, muscle growth remains restricted (Baker et al., 2010). These results indicate that the relationship between the developmental trajectories of brain and muscle tissues differ among those affected by IUGR. In addition, the relative impact of fetal growth on muscle mass later in life is not insignificant. The effect size of being born LBW on muscle mass in men ∼65 years of age was estimated as 4.4 kg less muscle and 25% lower muscle/fat ratios when compared to a higher birth weight group (Kensara et al., 2005).

Several studies also have found positive associations between birthweight with later life muscle strength (Table 1), which raises the question as to whether reductions in fetal muscle mass contribute to sarcopenia, or the age-related decline in muscle mass, strength, and functional ability. Grip strength is commonly used as an indicator of muscle strength and is a predictor of morbidity and mortality (Rantanen et al., 2000). Sayer et al. pooled 10 independent articles that described the relationship between birthweight and grip strength and found a 2 kg increase in grip strength per kg increase in birthweight (Sayer et al., 2008). Another study comprehensively evaluated muscle strength and force generation in college-aged women born with a low ponderal index (representing low muscle mass) and found not only an 11% lower grip strength, but also a 9-24% lower capacity for maximal isometric contraction, a higher rate of fatigue, and a diminished training response (Brutsaert et al., 2011). This study and others adjusted for body size and fat free mass, with the goal of teasing apart the effects of fetal growth on morphological changes during muscle development as opposed to simply reflecting muscle mass. In most cases, adjusting for muscle mass attenuated the association between birthweight and muscle strength but did not eliminate it (Sayer et al., 2008), and it actually increased the strength of association between a low ponderal index and measures of muscle strength (Brutsaert et al., 2011). The most important contributing factors to how fetal growth impacts muscle growth, whether they be muscle mass, morphology, capacity for conditioning, and/or neuromuscular factors, have yet to be definitively determined.

It is important to note that all of these studies are associative and do not prove causality. There are many postnatal factors, even when the youngest children are evaluated, that impact body composition and muscle strength. While fat free mass and lean mass assessment is a good proxy for skeletal muscle mass, they include tissues other than muscle. Finally, birthweight is used as a surrogate for fetal growth patterns, because it is easily obtained from birth records and/or birth certificates for large populations of individuals. Definitive associations between placental insufficiency-induced IUGR and later life muscle mass will require prospective studies that measure umbilical arterial and middle cerebral artery Doppler velocimetry and novel methods to measure muscle mass more specifically. Comprehensive analysis of these relationships, including interventional studies that aim to improve the life trajectory of muscle growth, will require the use of animal models (discussed in Section 3.1) in addition to human clinical studies.

2.2 Reduced muscle-to-fat ratios

Interactions between birthweight, muscle mass, and fat mass have been demonstrated, such that birthweight strongly correlates with lean mass, but either does not correlate or is inversely correlated with fat mass in later life. This, in turn, can produce a reduced muscle-to-fat ratio. Excess adiposity and central (visceral) obesity are well known metabolic disease risk factors (Amato et al., 2013). However, excess adiposity in combination with low muscle mass, termed “sarcopenic obesity”, has emerged as an even more concerning phenotype for cardiometabolic disease risk (Prado et al., 2012). Reduced muscle-to-fat ratios were found by DXA in low birth weight (<3.2 kg) vs. high birth weight infants (>3.9 kg) in a cohort of Englishmen at 56-70 years of age (Kensara et al., 2005). Additionally, other studies have associated low birthweight with reduced waist-to-hip ratios, which is an anthropometric measure of central obesity and also might reflect gluteal muscle mass with the hip circumference (Table 1). Reduced muscle-to-fat ratios also have been implicated as a possible reason for the current diabetes epidemic in India. The “thin-fat” phenotype of Indian diabetic patients is characterized by less muscle mass but greater body fat and central obesity (Yajnik 2004a). Infants born in India compared to infants born in the United Kingdom are lighter, shorter, and thinner, but have similar subscapular skin fold thicknesses, suggesting that intrauterine growth patterns contribute to lower muscle mass but preserved fat mass in this population (Yajnik et al. 2003).

It is possible that persistent limitations in muscle growth and/or reduced muscle-to-fat ratios after placental insufficiency and IUGR set the trajectory for rapid catch-up growth that favors adiposity over muscle. The concept of “catch-up growth” is well described in the literature as the growth pattern of a deprived intrauterine environment and poor infant growth followed by rapid weight gain (Claris et al., 2010). Barker et al. were some of the first to show the potential impact of accelerated postnatal growth on cardiovascular risk. In this landmark study, individuals who were born SGA who then underwent rapid weight gain between ages 2 and 11 were at highest risk for adverse cardiovascular outcomes as adults (Barker et al., 2005). Other systematic reviews have identified rapid weight gain during the first year of life, regardless of birthweight, as a risk factor for childhood obesity (Ong et al., 2006, Weng et al., 2012). When postnatal growth patterns and body composition have been specifically evaluated in SGA children between ages 2 and 4 years, those born SGA gained more abdominal fat and body adiposity and less lean mass than AGA children; by age 4 years, SGA children had greater adiposity and insulin resistance (Ibanez et al., 2006). In a similar cohort, SGA children with rapid catch up growth transitioned from insulin sensitive to an insulin resistant phenotype (Mericq et al., 2005). Animal studies also have demonstrated an imbalance in lean versus fat accumulation in the catch-up growth process. Growth restricted lambs have accelerated postnatal growth driven by increases in adiposity and limited muscle growth (De Blasio et al., 2007, Greenwood et al., 2003), leading to 25% lower muscle/fat ratios at 9 months of age (Ford et al., 2007). In LBW mice that were undernourished in utero, those given a control diet and demonstrated catch-up growth developed obesity and glucose intolerance at 6 months of age, whereas those given a calorie-restricted diet 50% of that of controls were leaner and had better glucose tolerance (Jimenez-Chillaron et al., 2006). Similarly, increased catch-up growth after prenatal (Bieswal et al., 2006) and postnatal (Jou et al., 2013) growth restriction in rats resulted in higher fat mass and decreased protein content compared to those that did not catch up. Animal studies support that catch-up growth in the form of increased adiposity over lean mass plays an important, if not independent, role in the development of later life obesity (Jimenez-Chillaron et al., 2007, Morrison et al., 2010).

Despite a large body of literature that associates catch-up growth with the development of obesity and metabolic disease, the exact mechanisms by which catch-up growth occurs, including the potential role of reduced muscle-to-fat ratios in the development of metabolic disease, are still unknown. Also, it is important to note that the vast majority of SGA infants will demonstrate some degree of accelerated growth. Catch-up growth is beneficial for optimization of brain growth and neurodevelopment (Dusick et al., 2003, Lundgren et al., 2001, Ong, 2007) as well as for avoiding short stature (Karlberg et al., 1995). Consideration for gain in fat mass separately from gain in lean mass in future clinical studies will facilitate a better understanding of the roles of compensatory adiposity vs. muscle growth for overall health, metabolism, and neurodevelopment, and will aid in the development of nutritional strategies that achieve “healthy” catch-up growth.

2.3 Impaired glucose disposal, insulin resistance, and diabetes

Clear associations have been found between birth weight, insulin resistance, and the development of type 2 diabetes, as evidenced by a large meta-analysis which found inverse associations between birth weight and type 2 diabetes in 23 populations (Whincup et al., 2008). Barker et al. found an inverse relationship between birthweight and the metabolic syndrome (which includes insulin resistance, obesity, type 2 diabetes, hypertension, and hyperlipidemia) and a 22% incidence of the metabolic syndrome in those men whose birthweights were < 2900 grams (Barker et al., 1993). Rat models of IUGR have reproduced these relationships by demonstrate striking phenotypes in offspring of hyperinsulinemia, hyperglycemia, central obesity, and diabetes (Fernandez-Twinn et al., 2005, Simmons et al., 2001). Skeletal muscle is a major determinant of regulates whole-body insulin sensitivity and glucose disposal, as it accounts for 80% of insulin-stimulated glucose uptake (Wolfe, 2006). A large epidemiological study showed that higher muscle mass was associated with better insulin sensitivity and lower risk of pre- or overt diabetes (Srikanthan et al., 2011). Similarly, in a study of over 1100 men, insulin resistance was found to be a central abnormality in the metabolic syndrome, as were lower muscle mass and strength (Atlantis et al., 2009). As proof of principle, increasing the number, size, and function of myofibers in mice specifically resulted in decreased fat mass and increase glucose uptake (Harrison et al., 2008). Undoubtedly, there are several mechanisms that contribute to the developmental origins of adult metabolic disease. A reduction in the functional capacity of muscle to respond to insulin and dispose of glucose might be responsible, in part, for the development of later life obesity and diabetes in formerly IUGR individuals.

3. Potential strategies to improve muscle growth

3.1 Prenatal therapies

Currently, there are limited means of improving either whole body or skeletal muscle-specific growth in the IUGR fetus. Several attempts at improving fetal growth have been made, including bed rest, maternal oxygen delivery, and increasing maternal nutrient delivery (ACOG, 2013). Balanced protein-calorie supplementation to high risk mothers was shown to increase birth weight by 41 grams (Rush et al., 1980); however, whether the additional fetal weight added was in the form of lean mass or adiposity was not determined. Prenatal treatments to improve fetal growth are still worth pursuing, as it was estimated from a cohort of over 13,000 men and women that increasing birth weight and minimizing accelerated postnatal growth could reduce diabetes risk by 57% and the incidence of hypertension and coronary heart disease by 25% and 40%, respectively (Barker et al., 2002). This analysis did not take into account body composition, however, when growth was assessed, as strategies that simply accelerate adipose tissue growth might be counter-productive.

Insights into how fetal skeletal muscle restriction occurs can be determined using a well characterized sheep model of chronic and progressive placental insufficiency (Bell et al., 1987, Brown, 2014) (Figure 3). This model has the same fundamental characteristics of human IUGR (Barry et al., 2008), including elevated resistive indices in the umbilical artery (Galan et al., 2005), brain and heart growth that are relatively preserved (Anthony et al., 2003), and skeletal muscle weights normalized to limb length and brain weight that are reduced (unpublished observations). Fetal hypoxemia progressively becomes severe over gestation in this model (Regnault et al., 2007), with increased production of counter regulatory hormones (Yates et al., 2011). This model affords the capability to use chronic catheterization techniques (Maliszewski et al., 2012) to manipulate substrate and growth factor concentrations for prolonged periods of time during critical periods in myogenesis, including myoblast proliferation and myofiber hypertrophy (Fahey et al., 2005). Coinciding with these critical time periods, the IUGR fetus has reduced circulating insulin and IGF-1 concentrations (Brown et al., 2012, Macko et al., 2013, Thorn et al., 2009) and receives a reduced amino acid supply from the placenta (Brown et al., 2012, Ross et al., 1996) (Figure 3). Effects on fetal skeletal muscle growth specifically can be made by measuring femoral arterial-venous concentration differences, external iliac blood flow (Wilkening et al., 1994), and muscle-specific protein metabolic rates. Promisingly, short term amino acid infusion given directly to the fetus in this model increased protein accretion rates by suppressing protein breakdown rates (Brown et al., 2012).

Figure 3. Proposed mechanisms for reduced fetal skeletal muscle growth during conditions of placental insufficiency.

We propose that the combination of decreased growth factors and amino acids in the IUGR fetus leads to reduced rates of myoblast proliferation and myofiber hypertrophy, ultimately producing reductions in skeletal muscle mass. a) Normal fetal myogenesis and b) progressive decline in fetal insulin, IGF-1, and AA supply in a sheep model of placental insufficiency and IUGR. IUGR, intrauterine growth restriction; dGA, days gestation (term=145 dGA); ↔, no change.

3.2 Postnatal nutritional strategies

Until prenatal strategies to improve fetal growth are developed, those neonates who are born after IUGR, especially when born preterm, represent a nutritional challenge. Due to the lack of published data about the nutritional requirements of this population, recommendations for the nutritional management of the IUGR or SGA infant are not distinguished from AGA infants (Tudehope et al., 2013). However, current nutritional practices for the IUGR neonate do not target muscle growth but instead favor fat deposition (Gianni et al., 2009). Very limited data are available to guide the optimization of energy and protein balance in the IUGR infant, and studies are conflicting. Preterm SGA infants have higher metabolic rates and increased energy expenditure when compared to AGA infants in the first month of life (Bohler et al., 1999, Chessex et al., 1984, Davies et al., 1996). Some studies show that SGA infants are more efficient at protein gain (Cauderay et al., 1988, Van Goudoever et al., 1995), and others indicate that SGA infants have deficiencies in protein metabolism (Boehm et al., 1988, Boehm et al., 1998). We do not have a clear understanding of how to best provide nutrition to the IUGR neonate, especially when they are born preterm and require supplemental nutrition either by enteral or parenteral nutrition. It is reasonable to target nutritional strategies that optimize linear and skeletal muscle growth without inducing excess adiposity, such as by increasing protein delivery, and this is a critically important area of future investigation.

4. Conclusions

We have discussed several reasons for how reduced muscle mass in the context of placental insufficiency and IUGR might impact later life metabolic health. Fetal adaptations to placental insufficiency leave skeletal muscle vulnerable to reduced blood flow and nutrient delivery. Several phenotypic features of the IUGR fetus, including lower than normal plasma growth factor concentrations, adversely impact myogenesis. A large number of epidemiological studies consistently demonstrate strong correlations between birthweight and lean mass and muscle strength, which support the concept that reductions in muscle mass established by the intrauterine environment persist throughout the life span. Persistent restrictions in the capacity for muscle growth may contribute to postnatal growth patterns that produce a body composition with less than normal muscle mass and excessive adiposity, or at least a lower muscle-to-fat ratio. Furthermore, skeletal muscle itself facilitates glucose disposal and insulin sensitivity, and therefore reductions in muscle mass could predispose the IUGR individual to glucose intolerance, insulin resistance, and diabetes. Animal studies, in conjunction with human clinical studies, are needed for in depth examination of the mechanisms that restrict fetal and limit postnatal muscle growth, as well as to test nutritional strategies that might prevent the onset of later life metabolic disease.

Highlights.

• Placental insufficiency results in redistribution of fetal cardiac output to vital organs at the expense of muscle.

• Fetal myoblast proliferation and myotube hypertrophy are reduced in the IUGR fetus.

• Birthweight is positively correlated with lean mass and grip strength.

• Reduced fetal muscle mass in IUGR may set the trajectory for catch-up growth that favors adiposity.

• Nutritional strategies are needed to improve muscle growth and body composition in the IUGR fetus and neonate.