Selective expression of Cre recombinase in skeletal muscle fibers

Bothe, Gerald; Haspel, Jeffrey A.; Smith, Cynthia L.; Wiener, Heidi H.; Burden, Steven J.

doi:10.1002/(sici)1526-968x(200002)26:2<165::aid-gene22>3.0.co;2-f

Cited by 128 publications

(117 citation statements)

References 8 publications

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“…We crossed mice bearing floxed alleles of Cpt1b to Mlc1f-Cre transgenic mice for specific ablation of Cpt1b in skeletal muscle, but not cardiac tissue (28). Details of the Cpt1b targeting construct and crossing scheme to generate floxed mice are shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Impaired mitochondrial fat oxidation induces adaptive remodeling of muscle metabolism

Wicks

Vandanmagsar

Haynie

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

134

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The correlations between intramyocellular lipid (IMCL), decreased fatty acid oxidation (FAO), and insulin resistance have led to the hypothesis that impaired FAO causes accumulation of lipotoxic intermediates that inhibit muscle insulin signaling. Using a skeletal muscle-specific carnitine palmitoyltransferase-1 KO model, we show that prolonged and severe mitochondrial FAO inhibition results in increased carbohydrate utilization, along with reduced physical activity; increased circulating nonesterified fatty acids; and increased IMCLs, diacylglycerols, and ceramides. Perhaps more importantly, inhibition of mitochondrial FAO also initiates a local, adaptive response in muscle that invokes mitochondrial biogenesis, compensatory peroxisomal fat oxidation, and amino acid catabolism. Loss of its major fuel source (lipid) induces an energy deprivation response in muscle coordinated by signaling through AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) to maintain energy supply for locomotion and survival. At the whole-body level, these adaptations result in resistance to obesity.carnitine palmitoyltransferase | muscle | fatty acid | lipid | carbohydrate C onsiderable evidence suggests that when oversupply of dietary fat exceeds the storage capacity of adipose tissue, ectopic lipids accumulate in skeletal muscle, leading to "metabolic stress" that induces insulin resistance. One prevailing theory is that impaired skeletal muscle fatty acid oxidation (FAO) (1-4) leads to cytosolic accumulation of lipotoxic intermediates that are directly linked to defects in insulin signaling (5-11). Recent findings counter this premise because they have shown that models of insulin resistance consistently exhibit enhanced (not reduced) FAO, as demonstrated by elevated incomplete β-oxidation and accumulation of excess lipid-derived acylcarnitines (12, 13). Supporting evidence was obtained using a whole-body genetic approach to elevate levels of the endogenous carnitine palmitoyltransferase-1 (Cpt1) inhibitor, malonyl-CoA (12). These studies have led to the contrasting theory that lipid overload and incomplete FAO within the mitochondria accelerate the progression of insulin resistance (14). Faced with a plethora of studies supporting both hypotheses, a crucial question remains: "Is inhibition of mitochondrial FAO in skeletal muscle sufficient to initiate development of insulin resistance?" Cpt1 is essential for long-chain acyl-CoA transport into the mitochondria, and lies at the nexus of both the lipotoxicity and the mitochondrial overload hypotheses. If decreased FAO is a root cause of lipotoxicity, then muscle-specific ablation of Cpt1b activity should lead to impaired FAO, intramyocellular lipid (IMCL) accumulation, and insulin resistance. In stark contrast, the mitochondrial overload hypothesis suggests that decreased Cpt1b activity would preserve insulin sensitivity by preventing unbalanced overfueling of β-oxidation. Characterization of the rare genetic disorders o...

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Section: Resultsmentioning

confidence: 99%

Impaired mitochondrial fat oxidation induces adaptive remodeling of muscle metabolism

Wicks

Vandanmagsar

Haynie

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

134

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“…Residual SirT1 activity was expected from any nonmuscular tissues and muscle fibers not expressing MLCf1. It has been estimated that 45% of the nuclei within skeletal muscle tissue is within muscle cells, whereas the remaining nuclei are composed of other tissue types such as adipocytes, fibroblasts, and Schwann cells (26). SirT1 activity was measured using an in vitro SirT1 fluorometric assay (Biomol) as described by the manufacturer and as done previously (27).…”

Section: Methodsmentioning

confidence: 99%

Sirtuin 1-mediated Effects of Exercise and Resveratrol on Mitochondrial Biogenesis

Menzies

Singh

Saleem

et al. 2013

Journal of Biological Chemistry

140

133

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Background: SirT1 regulates mitochondrial biogenesis in various tissues. Results: Exercise combined with resveratrol has a SirT1-dependent synergistic effect on mitochondrial biogenesis, despite individual treatments being SirT1-independent. Conclusion: SirT1 is important for maintaining muscle mitochondrial content and function. Significance: The dependence of muscle mitochondrial biogenesis on SirT1 depends on the metabolic state of the muscle.

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“…CnB1-LoxP mice are described elsewhere (35), and NFAT luciferase reporter mice (NFAT site from the interleukin-4 promoter) have also been previously described (36). Mice expressing Cre recombinase under the control of the myosin light chain 1f (MLC1f) genomic locus (knock-in) were generously provided by Steven Burden (Skirball Institute, NYU) and were previously described (37). ␤-MyHCcre transgenic mice were generated that express the Cre recombinase in slow skeletal and embryonic cardiac muscle.…”

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confidence: 99%

Genetic Loss of Calcineurin Blocks Mechanical Overload-induced Skeletal Muscle Fiber Type Switching but Not Hypertrophy

Parsons

Millay

Wilkins

et al. 2004

Journal of Biological Chemistry

164

162

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The serine/threonine phosphatase calcineurin is an important regulator of calcium-activated intracellular responses in eukaryotic cells. In higher eukaryotes, calcium/ calmodulin-mediated activation of calcineurin facilitates direct dephosphorylation and nuclear translocation of the transcription factor nuclear factor of activated T-cells (NFAT). Recently, controversy has surrounded the role of calcineurin in mediating skeletal muscle cell hypertrophy. Here we examined the ability of calcineurin-deficient mice to undergo skeletal muscle hypertrophic growth following mechanical overload (MOV) stimulation or insulin-like growth factor-1 (IGF-1) stimulation. Two distinct models of calcineurin deficiency were employed: calcineurin A␤ gene-targeted mice, which show a Ϸ50% reduction in total calcineurin, and calcineurin B1-LoxP-targeted mice crossed with a myosin light chain 1f cre knock-in allele, which show a greater than 80% loss of total calcineurin only in skeletal muscle. Calcineurin A␤؊/؊ and calcineurin B1-LoxP(fl/fl)-MLC-cre mice show essentially no defects in muscle growth in response to IGF-1 treatment or MOV stimulation, although calcineurin A␤؊/؊ mice show a basal defect in total fiber number in the plantaris and a mild secondary reduction in growth, consistent with a developmental defect in myogenesis. Both groups of genetargeted mice show normal increases in Akt activation following MOV or IGF-1 stimulation. However, overloadmediated fiber-type switching was dramatically impaired in calcineurin B1-LoxP(fl/fl)-MLC-cre mice. NFAT-luciferase reporter transgenic mice failed to show a correlation between IGF-1-or MOV-induced hypertrophy and calcineurin-NFAT-dependent signaling in vivo. We conclude that calcineurin expression is important during myogenesis and fiber-type switching, but not for muscle growth in response to hypertrophic stimuli.

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Selective expression of Cre recombinase in skeletal muscle fibers

Cited by 128 publications

References 8 publications

Impaired mitochondrial fat oxidation induces adaptive remodeling of muscle metabolism

Impaired mitochondrial fat oxidation induces adaptive remodeling of muscle metabolism

Sirtuin 1-mediated Effects of Exercise and Resveratrol on Mitochondrial Biogenesis

Genetic Loss of Calcineurin Blocks Mechanical Overload-induced Skeletal Muscle Fiber Type Switching but Not Hypertrophy

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