Nuclear receptor/microRNA circuitry links muscle fiber type to energy metabolism

Gan, Zhenji; Rumsey, John W.; Hazen, Bethany C.; Lai, Ling; Leone, Teresa C.; Vega, Rick B.; Xie, Hui; Conley, Kevin E.; Auwerx, Johan; Smith, Steven R.; Olson, Eric N.; Kralli, Anastasia; Kelly, Daniel P.

doi:10.1172/jci67652

Cited by 178 publications

(246 citation statements)

References 54 publications

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“…Muscle ERRγ expression levels correlate with exercise performance in humans (36). Moreover, mice lacking ERRβ and ERRγ in skeletal muscle have decreased running capacity whereas mice overexpressing ERRγ in muscle show increased exercise capacity (36)(37)(38). We speculate that p38-mediated activation of ERRβ and ERRγ may link exercise to adaptive metabolic changes in skeletal muscle.…”

Section: Discussionmentioning

confidence: 89%

“…The MKK3/6 and p38 signaling cascade is activated in skeletal muscle by exercise, and p38γ is necessary for aspects of the adaptive response to exercise (34,35). Muscle ERRγ expression levels correlate with exercise performance in humans (36). Moreover, mice lacking ERRβ and ERRγ in skeletal muscle have decreased running capacity whereas mice overexpressing ERRγ in muscle show increased exercise capacity (36)(37)(38).…”

Section: Discussionmentioning

confidence: 99%

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GADD45γ regulates the thermogenic capacity of brown adipose tissue

Gantner

Hazen

Conkright

et al. 2014

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

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Significance Brown adipose tissue (BAT) specializes in converting stored chemical energy into heat. When activated in response to cold, BAT increases the body’s metabolic rate and promotes fat loss. The recent identification of BAT in humans makes activation of this tissue an attractive target for counteracting obesity. However, our understanding of the intracellular pathways that regulate the response to cold is limited. Here, we identify a previously unknown regulator of BAT activation, growth arrest and DNA-damage-inducible protein 45 γ, which is induced in response to cold and works via the MAPK p38 and the transcription factor estrogen-related receptor γ to enhance the expression of genes important for thermogenesis. Our findings may provide new avenues for the stimulation of energy expenditure.

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

GADD45γ regulates the thermogenic capacity of brown adipose tissue

Gantner

Hazen

Conkright

et al. 2014

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

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“…Fresh skeletal muscle tissues were isolated and immediately frozen in isopentane that had been cooled in liquid nitrogen. MyHC immunofluorescences were conducted as previously described (43). The fiber numbers and cross-sectional areas (CSAs) were then quantified (MyHCI, green; MyHCIIB, red) with Image J (NIH) software.…”

Section: Methodsmentioning

confidence: 99%

Regulation of DLK1 by the maternally expressed miR-379/miR-544 cluster may underlie callipyge polar overdominance inheritance

Gao

Chen

Wang

et al. 2015

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

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Inheritance of the callipyge phenotype in sheep is an example of polar overdominance inheritance, an unusual mode of inheritance. To investigate the underlying molecular mechanism, we profiled the expression of the genes located in the Delta-like 1 homolog (Dlk1)-type III iodothyronine deiodinase (Dio3) imprinting region in mice. We found that the transcripts of the microRNA (miR) 379/miR-544 cluster were highly expressed in neonatal muscle and paralleled the expression of the Dlk1. We then determined the in vivo role of the miR-379/miR-544 cluster by establishing a mouse line in which the cluster was ablated. The maternal heterozygotes of young mutant mice displayed a hypertrophic tibialis anterior muscle, extensor digitorum longus muscle, gastrocnemius muscle, and gluteus maximus muscle and elevated expression of the DLK1 protein. Reduced expression of DLK1 was mediated by miR-329, a member of this cluster. Our results suggest that maternal expression of the imprinted miR-379/miR-544 cluster regulates paternal expression of the Dlk1 gene in mice. We therefore propose a miR-based molecular working model for polar overdominance inheritance. muscle hypertrophy | callipyge | DLK1 | miR-379/miR-544 cluster T he callipyge (CLPG) phenotype can be characterized by an increase in muscle mass due to muscular hypertrophy and a unique non-Mendelian mode of inheritance (1-3). CLPG individuals are born with normal muscle histology and develop muscle hypertrophy at ∼1 mo of age. This hypertrophy occurs primarily in the muscles of the pelvic limbs and loin and some muscles in the shoulder, which are enriched with a high proportion of type IIB fast-twitch glycolytic fibers (4). Although the molecular regulation of these hypertrophic processes is yet to be determined, Delta-like 1 homolog (DLK1) is found to be the causative protein (5-10). The unique mode of inheritance of the CLPG phenotype has attracted a great deal of attention within the scientific community. The CLPG offspring inherit the phenotype only when the mutated allele comes from the father and the wild-type allele from the mother (CLPG PAT /+ MAT ). CLPG PAT /CLPG MAT offspring exhibit a wild-type phenotype, despite carrying a CLPG mutation on the paternal chromosome. This unusual mode of inheritance led to the development of the genetic concept of polar overdominance (2, 11).The CLPG mutation has been mapped to the Dlk1-Dio3 imprinted domain, which spans ∼1 Mb and harbors at least three protein-encoding genes, including Dlk1, Peg11/Rtl1, and Dio3, and multiple noncoding RNA genes, including Gtl2, anti-Peg11/anti-Rtl1, Meg8, Mirg, C/D small nucleolar RNAs (snoRNAs), and microRNA clusters [the microRNA (miR) 379 and miR-127 clusters] (12-14). The coding genes are expressed paternally, whereas the noncoding genes are expressed maternally (15,16). Further analysis revealed a point mutation (A to G transition) within the intergenic region between the Dlk1 and Gtl2 genes of the imprinted Dlk1-Dio3 region (17, 18), which affects a muscle-specific, long-range cis-acting ...

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“…Furthermore, in many transgenic mouse models, an increase in muscle mitochondrial oxidative capacity is associated with a shift to a more oxidative muscle fibertype composition. For example, mice with musclespecific overexpression of PGC-1a, PGC-1b, PPARd, or ERRg have increases in type I, IIa, or IIx fibers, at the expense of IIb fibers (with each transgenic model showing distinct patterns of fiber-type composition) (20)(21)(22)(23)(24)63). Some of these mouse models also show decreases in fiber cross-sectional area, consistent with a switch to more oxidative fibers (21,23).…”

Section: Ckmt2 Glut4 Cpt1b Fabp3mentioning

confidence: 96%

“…The coactivators PGC-1a and PGC-1b and the nuclear receptors ERRa and ERRg also drive skeletal muscle angiogenesis, at least in part via the induction of Vegfa (15)(16)(17). Changes in fiber-type composition are thought to be primarily under the control of NFAT, though they are also controlled by PGC-1a, PGC-1b, PPARd, and ERRb/ERRg (17)(18)(19)(20)(21)(22)(23)(24). Notably, many of these transcriptional regulators seem to work as a tightly knit network, crosstalking and regulating each other's expression.…”

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confidence: 99%

Perm1 enhances mitochondrial biogenesis, oxidative capacity, and fatigue resistance in adult skeletal muscle

et al. 2015

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Skeletal muscle mitochondrial content and oxidative capacity are important determinants of muscle function and whole‐body health. Mitochondrial content and function are enhanced by endurance exercise and impaired in states or diseases where muscle function is compromised, such as myopathies, muscular dystrophies, neuromuscular diseases, and age‐related muscle atrophy. Hence, elucidating the mechanisms that control muscle mitochondrial content and oxidative function can provide new insights into states and diseases that affect muscle health. In past studies, we identified Perm1 (PPARGC1‐ and ESRR‐induced regulator, muscle 1) as a gene induced by endurance exercise in skeletal muscle, and regulating mitochondrial oxidative function in cultured myotubes. The capacity of Perm1 to regulate muscle mitochondrial content and function in vivo is not yet known. In this study, we use adeno‐associated viral (AAV) vectors to increase Perm1 expression in skeletal muscles of 4‐wk‐old mice. Compared to control vector, AAV1‐Perm1 leads to significant increases in mitochondrial content and oxidative capacity (by 40‐80%). Moreover, AAV1‐Perm1‐transduced muscles show increased capillary density and resistance to fatigue (by 33 and 31 %, respectively), without prominent changes in fiber‐type composition. These findings suggest that Perm1 selectively regulates mitochondrial biogenesis and oxidative function, and implicate Perm1 in muscle adaptations that also occur in response to endurance exercise.—Cho, Y., Hazen, B. C., Gandra, P. G., Ward, S. R., Schenk, S., Russell, A. P., Kralli, A. Perm1 enhances mitochondrial biogenesis, oxidative capacity, and fatigue resistance in adult skeletal muscle. FASEB J. 30, 674‐687 (2016). http://www.fasebj.org

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Nuclear receptor/microRNA circuitry links muscle fiber type to energy metabolism

Cited by 178 publications

References 54 publications

GADD45γ regulates the thermogenic capacity of brown adipose tissue

GADD45γ regulates the thermogenic capacity of brown adipose tissue

Regulation of DLK1 by the maternally expressed miR-379/miR-544 cluster may underlie callipyge polar overdominance inheritance

Perm1 enhances mitochondrial biogenesis, oxidative capacity, and fatigue resistance in adult skeletal muscle

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