Regulation of Fetal Skeletal Muscle Growth in IUGR

PROJECT ABSTRACT
Our goal is to improve skeletal muscle growth and body composition in the fetus, neonate, and adult affected by
intrauterine growth restriction (IUGR). Fetal skeletal muscle growth is profoundly limited as a result of placental
insufficiency and leads to lifelong reductions in muscle mass (sarcopenia) and metabolic disease risk, making
restoration of muscle mass during the perinatal period a high priority. During the previous project period, we
found multiple defects in fetal skeletal muscle growth in a highly relevant sheep model of IUGR, including lower
muscle protein synthesis (MPS) rates, lower muscle mass relative to brain and whole-body weights, smaller
myofibers with lower myonuclear number, and fewer total myofibers compared to normally-growing controls.
Based on our preliminary data, we have identified adaptations within branched-chain amino acid (BCAA)
catabolism that result in lower MPS in the IUGR fetus. Weight-specific BCAA uptake rates by the IUGR hindlimb
are reduced despite normal circulating BCAA concentrations, the likely result of lower Na+K+-ATPase activity to
drive BCAA into the myocyte. Branched-chain aminotransferase (BCAT) protein expression is higher, which is
the first step in BCAA catabolism and results in de novo alanine and glutamine synthesis to support
gluconeogenesis, anapleurosis, and energy production. Despite our recent progress, however, critical
knowledge gaps remain regarding the mechanisms by which placental insufficiency programs the IUGR myocyte
to reduce BCAA uptake and increase BCAA catabolism. Furthermore, it is not known when during an IUGR
gestation these mechanisms become intrinsic to the myocyte or how they may be prevented and/or reversed to
improve muscle growth. We have assembled a research team of highly qualified experts in metabolism and
state-of-the-art metabolomic and proteomic techniques to fill these knowledge gaps. We will test the hypothesis
that lower Na+K+-ATPase and higher BCAT activity are intrinsic to the fetal myocyte to increase BCAA catabolism
and limit MPS by the end of an IUGR gestation, but that a targeted therapy (L-alanyl-L-glutamine, AG) delivered
during a critical developmental window will ameliorate these defects to increase MPS. In Aim 1, we will determine
the cellular mechanisms that reduce MPS and test the extent to which these adaptations are intrinsic to the
myocyte and/or induced by extrinsic circulating factors the IUGR fetus. In Aim 2, we will address when MPS
becomes limited during the course of an IUGR pregnancy. This information is critical to inform the timing of
therapies during pregnancy aimed to increase fetal growth. In Aim 3, we will test the capacity of an AG infusion
into the IUGR fetus to activate Na+K+-ATPase, stimulate BCAA uptake, and reverse BCAA catabolism to increase
intramuscular BCAA for MPS. In summary, this proposal will address gaps in knowledge about how BCAA
utilization is regulated in the fetus exposed to placental insufficiency when myofibers are forming, myonuclei are
accreting, and hypertrophy rates are some of the highest during the lifespan. These studies are a necessary
prerequisite for designing novel approaches to restore muscle growth.

Grant Number: 5R01HD079404-10
NIH Institute/Center: NIH
Principal Investigator: Laura Brown