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Heme deficiency in skeletal muscle exacerbates sarcopenia and impairs autophagy by reducing AMPK signaling
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Heme deficiency in skeletal muscle exacerbates sarcopenia and impairs autophagy by reducing AMPK signaling
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Journal Article
Heme deficiency in skeletal muscle exacerbates sarcopenia and impairs autophagy by reducing AMPK signaling
2024
Overview
Heme serves as a prosthetic group in hemoproteins, including subunits of the mammalian mitochondrial electron transfer chain. The first enzyme in vertebrate heme biosynthesis, 5-aminolevulinic acid synthase 1 (ALAS1), is ubiquitously expressed and essential for producing 5-aminolevulinic acid (ALA). We previously showed that
Alas1
heterozygous mice at 20–35 weeks (aged-
A1
+/−
s) manifested impaired glucose metabolism, mitochondrial malformation in skeletal muscle, and reduced exercise tolerance, potentially linked to autophagy dysfunction. In this study, we investigated autophagy in
A1
+/−
s and a sarcopenic phenotype in
A1
+/−
s at 75–95 weeks (senile-
A1
+/−
s). Senile-
A1
+/−
s exhibited significantly reduced body and gastrocnemius muscle weight, and muscle strength, indicating an accelerated sarcopenic phenotype. Decreases in total LC3 and LC3-II protein and
Map1lc3a
mRNA levels were observed in aged-
A1
+/−
s under fasting conditions and in
Alas1
knockdown myocyte-differentiated C2C12 cells (
A1
KD-C2C12s) cultured in high- or low-glucose medium. ALA treatment largely reversed these declines. Reduced AMP-activated protein kinase (AMPK) signaling was associated with decreased autophagy in aged-
A1
+/−
s and
A1
KD-C2C12s. AMPK modulation using AICAR (activator) and dorsomorphin (inhibitor) affected LC3 protein levels in an AMPK-dependent manner. Our findings suggest that heme deficiency contributes to accelerated sarcopenia-like defects and reduced autophagy in skeletal muscle, primarily due to decreased AMPK signaling.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
5-Aminolevulinate Synthetase - genetics
/ 5-Aminolevulinate Synthetase - metabolism
/ 5-aminolevulinic acid synthase 1 (ALAS1)
/ 631/337
/ 631/80
/ Aminoimidazole Carboxamide - analogs & derivatives
/ Aminoimidazole Carboxamide - pharmacology
/ Aminolevulinic Acid - pharmacology
/ AMP-activated protein kinase
/ AMP-Activated Protein Kinases - metabolism
/ Animals
/ Heme
/ Humanities and Social Sciences
/ Kinases
/ Male
/ Mice
/ mRNA
/ Muscle, Skeletal - metabolism
/ Muscle, Skeletal - pathology
/ Myocytes
/ Proteins
/ Ribonucleotides - pharmacology
/ Science
