Abstract
BackgroundAs a cellular energy sensor, the 5’AMP-activated protein kinase (AMPK) is activated in response to energy stresses such as hypoxia and muscle contraction. To determine effects of iron deficiency on AMPK activation and signaling, as well as the AMPK subunit composition in skeletal muscle, rats were fed a control (C=50-58 mg/kg Fe) or iron deficient (ID=2-6 mg/kg Fe) diet for 6–8 wks.ResultsTheir respective hematocrits were 47.5% ± 1.0 and 16.5% ± 0.6. Iron deficiency resulted in 28.3% greater muscle fatigue (p<0.01) in response to 10 min of stimulation (1 twitch/sec) and was associated with a greater reduction in phosphocreatine (C: Resting 24.1 ± 0.9 μmol/g, Stim 13.1 ± 1.5 μmol/g; ID: Resting 22.7 ± 1.0 μmol/g, Stim 3.2 ± 0.7 μmol/g; p<0.01) and ATP levels (C: Resting 5.89 ± 0.48 μmol/g, Stim 6.03 ± 0.35 μmol/g; ID: Resting 5.51 ± 0.20 μmol/g, Stim 4.19 ± 0.47 μmol/g; p<0.05). AMPK activation increased with stimulation in muscles of C and ID animals. A reduction in Cytochrome c and other iron-dependent mitochondrial proteins was observed in ID animals (p<0.01). The AMPK catalytic subunit (α) was examined because both isoforms are known to play different roles in responding to energy challenges. In ID animals, AMPKα2 subunit protein content was reduced to 71.6% of C (p<0.05), however this did not result in a significant difference in resting AMPKα2 activity. AMPKα1 protein was unchanged, however an overall increase in AMPKα1 activity was observed (C: 0.91 pmol/mg/min; ID: 1.63 pmol/mg/min; p<0.05). Resting phospho Acetyl CoA Carboxylase (pACC) was unchanged. In addition, we observed significant reductions in the β2 and γ3 subunits of AMPK in response to iron deficiency.ConclusionsThis study indicates that chronic iron deficiency causes a shift in the expression of AMPKα, β, and γ subunit composition. Iron deficiency also causes chronic activation of AMPK as well as an increase in AMPKα1 activity in exercised skeletal muscle.
Highlights
As a cellular energy sensor, the 5’AMP-activated protein kinase (AMPK) is activated in response to energy stresses such as hypoxia and muscle contraction
The objective of this study was to examine: 1) the extent to which chronic AMPactivated protein kinase (AMPK) activation occurs due to iron deficiency, 2) how AMPK activation and signaling due to muscle stimulation is affected during iron deficiency, and 3) the effects of iron deficiency on the AMPK subunit composition in skeletal muscle
After establishing that the ID rats were iron deficient and that this did create a metabolic stress, we examined the effects of chronic iron deficiency and in situ muscle stimulation on activation of the two AMPKα isoforms
Summary
As a cellular energy sensor, the 5’AMP-activated protein kinase (AMPK) is activated in response to energy stresses such as hypoxia and muscle contraction. Iron is important for oxygen transport and ATP synthesis If these processes are impaired by iron deficiency, cellular adaptations occur, such as an increased glucose dependence, in response to that deficiency [1,2]. Iron deficiency is a metabolic stress because it compromises both the capacity for oxygen supply to tissues (anemia), as well as the capacity to utilize oxygen due to impairment of mitochondrial capacity [5]. This type of energetic stress, due to either decreased oxygen supply or utilization, has been shown to cause an increase in AMPK activation [6]
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