Stage of perinatal development regulates skeletal muscle mitochondrial biogenesis and myogenic regulatory factor genes with little impact of growth restriction or cross-fostering.
Summary (2 min read)
Introduction
- Being born small for gestational age significantly increases the risk of developing insulin resistance and type 2 diabetes later in life.
- The impact of foetal growth restriction on markers of skeletal muscle mitochondrial biogenesis and the developmental time course in early life remains unclear.
- 29–32 Myogenic differentiation 1 (MyoD), myogenin and MRF4 are involved in skeletal muscle proliferation and differentiation with expression detected from mid-to-late gestation.
- An insult, during gestation or after birth, may alter the expression of these myogenic regulatory and growth factors and may impact on later skeletal muscle mass and function.
- 4,42–44 Indeed, Siebel et al. have shown that improved postnatal nutrition by crossfostering growth-restricted pups onto a control mother with normal lactation, improved early postnatal growth and ameliorated the impaired glucose tolerance45 and pancreatic b-cell mass46 observed at 6 months of age.
Animals
- All procedures were approved by The University of Melbourne Animal Experimentation Sub-Committee.
- Bilateral uterine vessel ligation of both the artery and vein supplying each uterine horn was performed to induce late gestation uteroplacental insufficiency or sham surgery was performed to generate the Control group.
- Foetuses at E20 or pups at postnatal day 1 (PN1) and 7 (PN7) were weighed, killed by decapitation and hindlimb skeletal muscle rapidly excised, pooled within litters and separated by sex (n 5 8–10 litters/group).
- Depending on probe availability, real-time PCR using either SYBR green8 or TaqMan R 52 chemistry was performed, as described previously, using the sequence detector software (Rotor-gene v6, Corbett Research, Sydney, NSW, Australia).
- For the Developmental Timeline Study, gene expression data were analysed separately for sex using a two-way ANOVA for age and treatment.
Weights and dimensions
- The effect of uteroplacental insufficiency and cross-fostering on body weight and dimensions in the male cohort has previously been published.
- Skeletal muscle gene expression Skeletal muscle mitochondrial biogenesis markers PGC-1a mRNA was similar for all groups regardless of the postnatal environment (Fig. 3a and 3d).
- In general, there were few effects of foetal growth restriction or cross-fostering on MyoD, myogenin and MRF4 mRNA in males and females (Fig. 4a–4c and 4e–4g, respectively).
- Consistent with data from Study 1, female Rest-on-Rest MyoD expression was higher (P , 0.05) compared with Cont-on-Cont offspring (Fig. 4e).
- In females, fostering control pups onto a restricted mother (Cont-on-Rest) with impaired lactation lowered (P , 0.05) IGF-I mRNA compared with Rest-on-Rest females (Fig. 4h).
Discussion
- These studies have shown that skeletal muscle gene expression of mitochondrial biogenesis markers and myogenic regulatory and growth factors display age-dependent expression patterns throughout development.
- Surprisingly, there was a remarkably small effect of growth restriction and cross-fostering.
- 53–55 Interestingly, the gene expression profile of Tfam, the transcription factor responsible for mtDNA replication, is not reflective of the PGC-1a and COX IV expression profiles.
- 27,29 Finally, the higher expression of IGF-I from gestation to at least PN7 may reflect its role in early skeletal muscle development and growth,39 which is then downregulated by the early juvenile period when skeletal muscle differentiation is complete.
The impact of uteroplacental insufficiency (Study 1)
- Following uteroplacental insufficiency and growth restriction, skeletal muscle markers of mitochondrial biogenesis were largely intact during late gestation and postnatal life.
- The impact of foetal growth restriction on skeletal muscle mitochondrial biogenesis and its time course in the perinatal period remains unclear.
- COX III is a mitochondrial-encoded protein, whereas COX IV is a nuclear-encoded protein, both involved in the electron transfer chain on the inner mitochondrial membrane and, therefore, the upregulation of COX III and IV mRNA may contribute to increased electron transfer chain components to improve mitochondrial respiration.
- How this will impact on the adult skeletal muscle metabolic profile is unknown, but as cross-fostering has been associated with improved glucose tolerance in adulthood of small birth weight rats,45 the gene changes in skeletal muscle may also contribute to improved adult health.
- It appears that expression is altered in both males and females when the pre- and postnatal nutritional environments were mismatched and was associated with specific changes in body weight and dimensions.
Summary
- The current studies have shown that skeletal muscle markers of mitochondrial biogenesis remain intact in early life following foetal growth restriction despite their previous data showing marked impairments at 6 months of age in males.
- It is therefore likely that the deficits in mitochondrial biogenesis develop later in life.
- Indeed, the upregulation of MyoD and IGF-I following foetal growth restriction may be indicative of delayed myogenesis in a sex-specific manner.
- Improved postnatal nutrition by cross-fostering improved growth in males early in life and was associated with upregulation of the electron transfer chain proteins, COX III and IV in small birth weight males and females.
- Whether these subtle changes will have consequences for later disease outcomes in adulthood are unknown.
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References
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...Insulin-like growth factor I (IGF-I) plays a welldefined role in skeletal muscle hypertrophy, but evidence also implicates IGF-I in skeletal muscle proliferation and differentiation.(39) Owing to the temporal pattern of MRF expression, the timing of an insult may be an important determinant of the muscle’s phenotypic profile....
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Frequently Asked Questions (15)
Q2. How much of the skeletal muscle in the human is undifferentiated?
skeletal muscle differentiation in the human does continue after birth with up to 20% of fibres undifferentiated in the newborn, which drops to adult levels by 1 year of age.
Q3. What is the effect of a uterine growth restriction on skeletal muscle development?
Their laboratory has shown that foetal growth restriction reduces gene and protein markers of skeletal muscle mitochondrial biogenesis [e.g. peroxisome proliferator-activated receptor (PPAR)-g coactivator-1a (PGC-1a), mitochondrial transcription factor A (Tfam), cytochrome c oxidase subunits 3 and 4 (COX III and IV)] in 6-month-old adult rats, with males more affected than females.
Q4. What is the effect of uteroplacental insufficiency on the development?
Their laboratory has shown that uteroplacental insufficiency in pregnant rats not only impairs the growth of the foetus but also impairs maternal mammary development resulting in poor lactation,40 further compromising the growth of the offspring after birth.
Q5. What is the role of the master regulator of mitochondrial biogenesis in the development of skeletal?
One study reported that the master regulator of mitochondrial biogenesis, PGC1a, mRNA was downregulated in the slow twitch soleus muscle but upregulated in the fast twitch extensor digitorum longus muscle of small birth weight offspring at 21 days of age, with males more affected than females.
Q6. What is the effect of cross-fostering on the development of rat pups?
Cross-fostering Restricted pups onto a Control mother significantly increased COX III mRNA in males and COX IV mRNA in both sexes above controls with little effect on other genes.
Q7. What is the role of age in regulating skeletal muscle development?
Developmental age appears to be a major factor regulating skeletal muscle mitochondrial and developmental genes, with growth restriction and cross-fostering having only subtle effects.
Q8. What was the RNA extracted from the skeletal muscle of the Cross-foster Study?
Analysis for studies 1 and 2: real-time polymerase chain reaction (PCR) analysisFor the Developmental Timeline Study, total RNA was extracted from skeletal muscle using the Tri-Reagent (Ambion Inc., Austin, TX, USA) method due to the small amounts of pooled tissue obtained from pups at E20 and PN1.
Q9. What is the effect of cross-fostering on the adult skeletal muscle?
How this will impact on the adult skeletal muscle metabolic profile is unknown, but as cross-fostering has been associated with improved glucose tolerance in adulthood of small birth weight rats,45 the gene changes in skeletal muscle may also contribute to improved adult health.
Q10. What is the effect of cross-fostering on the skeletal muscle?
Whether these relatively minor gene changes following cross-fostering will contribute to later disease prevention, observed at 6 months of age,45,46,51 is unclear; but perhaps an intervention that occurs at an age when deficits in skeletal muscle mitochondrial biogenesis markers are present would provide greater benefits to improved skeletal muscle mitochondrial biogenesis and insulin sensitivity.
Q11. How long did Costello et al.24 report that a reduced myofi?
more recently Costello et al.24 reported that following late gestation undernutrition in sheep, reduced myofibre density was associated with a compensatory upregulation of the IGF-I receptor at127 days gestation (term 147 days).
Q12. How long does it take to grow a rat to develop an adult metabolic disease?
In low birth weight humans, improved growth between birth and 2 years has been shown to reduce the risk of developing adult metabolic disease.
Q13. What is the impact of intrauterine growth restriction on skeletal muscle development?
On the basis ofour and others findings in adulthood, the authors hypothesized that key genes involved in skeletal muscle development and mitochondrial biogenesis would be altered following intrauterine growth restriction in rats, with different developmental profiles between males and females.
Q14. What is the impact of the reduced litter size on skeletal muscle markers?
It is important to consider that the control group used in these studies had their litter size reduced at birth,10,11 previously shown to alter postnatal growth and impair skeletal muscle markers of mitochondrial biogenesis at 6 months of age8 and therefore impacts on the interpretation of these findings.
Q15. What is the effect of uteroplacental insufficiency on skeletal?
It was particularly surprising to find that foetal growth restriction had no impact on PGC-1a gene expression as uteroplacental insufficiency causes foetal hypoxia and in skeletal muscle the hypoxia inducible factor 1 activity and expression is tightly coupled to PGC-1a.60