Maternal Creatine Supplementation during Pregnancy Prevents Long-Term Changes in Diaphragm Muscle Structure and Function after Birth Asphyxia

Abstract

Using a model of birth asphyxia, we previously reported significant structural and functional deficits in the diaphragm muscle in spiny mice, deficits that are prevented by supplementing the maternal diet with 5% creatine from mid-pregnancy. The long-term effects of this exposure are unknown. Pregnant spiny mice were fed control or 5% creatine-supplemented diet for the second half of pregnancy, and fetuses were delivered by caesarean section with or without 7.5 min of in-utero asphyxia. Surviving pups were raised by a cross-foster dam until 33±2 days of age when they were euthanized to obtain the diaphragm muscle for ex-vivo study of twitch tension and muscle fatigue, and for structural and enzymatic analyses. Functional analysis of the diaphragm revealed no differences in single twitch contractile parameters between any groups. However, muscle fatigue, induced by stimulation of diaphragm strips with a train of pulses (330ms train/sec, 40Hz) for 300sec, was significantly greater for asphyxia pups compared with controls (p<0.05), and this did not occur in diaphragms of creatine + asphyxia pups. Birth asphyxia resulted in a significant increase in the proportion of glycolytic, fast-twitch fibres and a reduction in oxidative capacity of Type I and IIb fibres in male offspring, as well as reduced cross-sectional area of all muscle fibre types (Type I, IIa, IIb/d) in both males and females at 33 days of age. None of these changes were observed in creatine + asphyxia animals. Thus, the changes in diaphragm fatigue and structure induced by birth asphyxia persist long-term but are prevented by maternal creatine supplementation.

Renal dysfunction in early adulthood following birth asphyxia in male spiny mice, and its amelioration by maternal creatine supplementation during pregnancy

“…These included neurodegenerative disorders and myopathies (37). Indeed, in the spiny mouse model of birth asphyxia we have demonstrated that maternal creatine supplementation during gestation also minimizes neural injury (17), damage to the diaphragm muscle (18,38) and deleterious remodeling of the skeletal musculature (39).…”

Evaluation of 3K3A-Activated Protein C to Treat Neonatal Hypoxic Ischemic Brain Injury in the Spiny Mouse

“…Intrapartum asphyxia was induced at 38 days of gestation (term at 39 days) as previously described [17][18][19][20][21][22]. Briefly, pregnant dams were killed via cervical dislocation.…”

“…This study used the precocial spiny mouse to study the effects of intrapartum asphyxia on the brain [17][18][19][20][21][22]. The spiny mouse differs from conventional laboratory rodents (mice, rats) in that considerable brain maturation (including the beginnings of myelination) occurs in utero before birth [47]; hence, acute hypoxia delivered during the intrapartum period can be used as a model of oxygen starvation that occurs at birth in some human pregnancies.…”

“…Using a well-validated model of intrapartum asphyxia in the spiny mouse [17][18][19][20][21][22], we investigated the effects of 3K3A-APC treatment on the neuropathology that follows brief asphyxia, in comparison with vehicle (saline) or wtAPC treatments. Specifically, our aim was to assess the cerebral effects of 3K3A-APC in both the gray and white matter by examining markers of neuro-inflammation and cell death.…”

Antenatal prevention of cerebral palsy and childhood disability: is the impossible possible?

“…A particular benefit in relation to CP is not only the decrease in severity of brain damage, but also the protection of skeletal muscle fibres and improved resistance to fatigue in the diaphragm (LaRosa et al . ). Neonatal acute kidney injury, which has a high prevalence in neonates that have experienced intrapartum hypoxia and is a co‐morbidity associated with poor neurological outcomes due to the acid–base and electrolyte imbalance (Perlman et al .…”