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Mitochondrial enzyme deficiency may underlie myopathic phenotype of female muscle‐specific LKB1‐KO mice
Author(s) -
Mongillo Anthony D.,
Malan Brandon B.,
Kenney Steven G.,
Brough Timise A.,
Winder William W.,
Thomson David M.
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.782.7
Subject(s) - medicine , endocrinology , mitochondrial biogenesis , cytochrome c oxidase , skeletal muscle , knockout mouse , mitochondrion , citrate synthase , biology , chemistry , enzyme , biochemistry , receptor
LKB1 and its target, AMPK, are regulators of muscle metabolism and play an important role in the control of mitochondrial biogenesis. Mitochondrial dysfunction leads to myopathic conditions in rodents and humans. We report here that the muscle‐specific knockout of LKB1 (KO) in female mice leads to a dysfunctional muscle phenotype and signs of congestive heart failure similar to other mitochondrial myopathies. At 9‐11 mo. of age, body weight (BW) was lower (p = 0.05) for KO vs control littermate (C) mice (21.6 ± 0.7 vs 26.2 ± 0.6 g). Absolute gastrocnemius (GAST) weight was lower for KO vs C mice (77.3 ± 2.9 vs 101.1 ± 3.7 mg), but not different as expressed relative to BW. Heart (HRT) weight relative to BW was greater in KO vs C mice (5.6 ± 0.3 vs 4.4 ± 0.1 mg). Cytochrome C (CytoC) and UCP‐2 levels were 40.1% and 59.3% lower, respectively, in KO vs C GAST muscles. CytoC, UCP‐2, UCP‐3, and cytoC oxidase‐1 (COX‐1) were all significantly lower in KO vs C HRT (33.8%, 50.8%, 49.5%, and 61.1% lower, respectively). Phosphorylation of CREB, one transcription factor controlling the expression of mitochondrial enzymes, was also decreased in HRT (40.1%) and GAST (35.6%) of KO vs C mice. Our findings suggest that impaired mitochondrial function may underlie the myopathic phenotype of LKB1‐deficient mice. This study was supported by National Institute of Arthritis and Musculoskeletal and Skin Diseases Grant AR‐051928.