Fnip1 regulates skeletal muscle fiber type specification, fatigue resistance, and susceptibility to muscular dystrophy

Reyes, Nicholas; Banks, Glen B.; Tsang, Mark; Margineantu, Daciana; Gu, Haiwei; Djukovic, Danijel; Chan, Jacky; Torres, Michelle; Liggitt, H. Denny; Hirenallur-S, Dinesh K; Hockenbery, David M.; Raftery, Daniel; Iritani, Brian M.

doi:10.1073/pnas.1413021112

Cited by 97 publications

(117 citation statements)

References 45 publications

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“…Skeletal muscle from homozygous Fnip1 mutants was also darker in color than heterozygous or wild-type littermates (Fig. 4A), as has been reported previously (9).…”

Section: Resultssupporting

confidence: 85%

“…Our investigation of the hamel allele reinforces the nonredundant roles of FNIP1 in B-cell development (7,8), skeletal muscle composition (9), and cardiac function (6). We reveal that BCL2 overexpression can partially, but not entirely, rescue B-cell development in the absence of FNIP1, and we provide evidence that FNIP1 is an endogenous negative regulator of AMPK.…”

Section: Discussionsupporting

confidence: 69%

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Mutation of Fnip1 is associated with B-cell deficiency, cardiomyopathy, and elevated AMPK activity

Siggs

Stockenhuber

Deobagkar-Lele

et al. 2016

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

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Folliculin (FLCN) is a tumor-suppressor protein mutated in the BirtHogg-Dubé (BHD) syndrome, which associates with two paralogous proteins, folliculin-interacting protein (FNIP)1 and FNIP2, forming a complex that interacts with the AMP-activated protein kinase (AMPK). Although it is clear that this complex influences AMPK and other metabolic regulators, reports of its effects have been inconsistent. To address this issue, we created a recessive lossof-function variant of Fnip1. Homozygous FNIP1 deficiency resulted in profound B-cell deficiency, partially restored by overexpression of the antiapoptotic protein BCL2, whereas heterozygous deficiency caused a loss of marginal zone B cells. FNIP1-deficient mice developed cardiomyopathy characterized by left ventricular hypertrophy and glycogen accumulation, with close parallels to mice and humans bearing gain-of-function mutations in the γ2 subunit of AMPK. Concordantly, γ2-specific AMPK activity was elevated in neonatal FNIP1-deficient myocardium, whereas AMPK-dependent unc-51-like autophagy activating kinase 1 (ULK1) phosphorylation and autophagy were increased in FNIP1-deficient B-cell progenitors. These data support a role for FNIP1 as a negative regulator of AMPK.irt-Hogg-Dubé (BHD) syndrome is a hereditary condition caused by germ-line or somatic mutations of the folliculin (FLCN) tumor-suppressor gene (1) and characterized by cutaneous hamartomas, pulmonary cysts, and an increased risk of renal cancer (2).FLCN forms a complex with paralogous folliculin interacting proteins, folliculin-interacting protein (FNIP)1 and FNIP2, both of which bind the C terminus of FLCN with the potential to form homo-or heterotrimeric multimers (3-5). FLCN is a nonredundant component of the FLCN/FNIP1/FNIP2 complex, whereas FNIP1 and FNIP2 appear to be functionally redundant in several tissues. This distinction is illustrated by the fact that kidney-specific deletion of mouse Flcn or compound deletion of Fnip1 and Fnip2 is sufficient to cause renal tumors, and yet deletions of Fnip1 or Fnip2 alone are not (6). This redundancy is consistent with the equivalent expression of Fnip1 and Fnip2 mRNA in kidney tissue (6). In contrast, FNIP1 is nonredundant in other tissues, including bone marrow, myocardium, and skeletal muscle: all of which express relatively more Fnip1 than Fnip2 (6-9).FNIP1 and FNIP2 also bind to the α, β, and γ subunits of the heterotrimeric AMP-activated protein kinase (AMPK) complex (3, 4). A critical regulator of cellular metabolism, AMPK senses and is activated by increased concentrations of AMP and ADP in the energy-depleted cell and subsequently phosphorylates an array of regulatory targets to restore cellular energy status (10). The multifaceted roles of AMPK include growth suppression by inhibiting synthesis of cellular macromolecules, in particular, through phosphorylation of the TSC2 tumor suppressor and inhibition of the mammalian target of rapamycin complex (mTORC)1 signaling pathway (11). AMPK also promotes autophagy via multiple pathways including mTORC1...

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“…Skeletal muscle from homozygous Fnip1 mutants was also darker in color than heterozygous or wild-type littermates (Fig. 4A), as has been reported previously (9).…”

Section: Resultssupporting

confidence: 85%

Section: Discussionsupporting

confidence: 69%

Mutation of Fnip1 is associated with B-cell deficiency, cardiomyopathy, and elevated AMPK activity

Siggs

Stockenhuber

Deobagkar-Lele

et al. 2016

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

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“…Although the genetic basis of skeletal muscle MHC isoform specification is an active area of research (e.g., ref. 16), the magnitude of the chimpanzeehuman contrast in MHC I fibers appears to exceed the more modest shifts that may be induced through intense athletic training (∼10-15%) (17,18). Furthermore, characterization of fiber-type distributions in the muscles of lemurs, galagos, and macaques suggests that a predominance of MHC II (IIa + IId) isoforms (i.e., fast fibers) is common among primates, as well as other terrestrial mammals (SI Appendix, SI Methods and Table S5).…”

Section: Resultsmentioning

confidence: 99%

Chimpanzee super strength and human skeletal muscle evolution

O’Neill

Umberger

Holowka

et al. 2017

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

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Since at least the 1920s, it has been reported that common chimpanzees (Pan troglodytes) differ from humans in being capable of exceptional feats of "super strength," both in the wild and in captive environments. A mix of anecdotal and more controlled studies provides some support for this view; however, a critical review of available data suggests that chimpanzee mass-specific muscular performance is a more modest 1.5 times greater than humans on average. Hypotheses for the muscular basis of this performance differential have included greater isometric force-generating capabilities, faster maximum shortening velocities, and/or a difference in myosin heavy chain (MHC) isoform content in chimpanzee relative to human skeletal muscle. Here, we show that chimpanzee muscle is similar to human muscle in its single-fiber contractile properties, but exhibits a much higher fraction of MHC II isoforms. Unlike humans, chimpanzee muscle is composed of ∼67% fast-twitch fibers (MHC IIa+IId). Computer simulations of species-specific whole-muscle models indicate that maximum dynamic force and power output is 1.35 times higher in a chimpanzee muscle than a human muscle of similar size. Thus, the superior mass-specific muscular performance of chimpanzees does not stem from differences in isometric force-generating capabilities or maximum shortening velocities-as has long been suggested-but rather is due in part to differences in MHC isoform content and fiber length. We propose that the hominin lineage experienced a decline in maximum dynamic force and power output during the past 7-8 million years in response to selection for repetitive, low-cost contractile behavior.chimpanzee | human | muscle | myosin heavy chain | muscle modeling M odern humans-with some exceptions-are often characterized as a weak and unathletic species compared with our closest living relatives, the chimpanzees. Whereas chimpanzees are proficient tree climbers and arborealists (1), our hominin ancestors gave up a reliance on the forest canopy after the emergence of the genus Homo (2). Subsequent evolution in brain size (3) and cognition as well as advancements in tools and other material culture (4, 5) have reduced our strict dependence on muscular strength for survival and fitness.Since at least the 1920s, both anecdotal reports and more controlled experiments have indicated that the strength of a chimpanzee can exceed that of a human (6-12). This has led to the now long-standing proposal that chimpanzees are "super strong" compared with humans. A critical review of experiments (i.e., pulling and jumping tasks) carried out between 1923 and 2014 suggests that chimpanzee mass-specific muscular performance consistently exceeds that of humans, with a differential of about 1.5 times, on average (SI Appendix, SI Discussion). Hypotheses for the muscular basis of the chimpanzee-human performance differential have included higher isometric force-producing capabilities (6-8, 11), faster maximum shortening velocities (7, 11), and/or a different distribution of myosin ...

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“…As a consequence, Adipoq-FLCN-null mice are more resistant to HFD-induced obesity due to the metabolic reprogramming of WAT, increasing lipid oxidation over storage in addition to stimulating the mitochondrial potential of BAT, again favoring fat burning. Similarly, loss of Fnip1, which belongs to the FLCN/FNIP/AMPK complex, results in chronic AMPK activation and increased oxidative metabolism in β cells and skeletal muscle in an AMPK/PGC1α-dependent manner (Park et al 2012;Reyes et al 2015). Discovery of pharmacological tools designed to inhibit FLCN expression or interfere with the formation of the FLCN/FNIP/AMPK complex would therefore be of great interest to treat obesity and other related metabolic disorders.…”

Section: Discussionmentioning

confidence: 99%

Chronic AMPK activation via loss of FLCN induces functional beige adipose tissue through PGC-1α/ERRα

et al. 2016

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The tumor suppressor folliculin (FLCN) forms a repressor complex with AMP-activated protein kinase (AMPK). Given that AMPK is a master regulator of cellular energy homeostasis, we generated an adipose-specific Flcn (Adipoq-FLCN) knockout mouse model to investigate the role of FLCN in energy metabolism. We show that loss of FLCN results in a complete metabolic reprogramming of adipose tissues, resulting in enhanced oxidative metabolism. Adipoq-FLCN knockout mice exhibit increased energy expenditure and are protected from high-fat diet (HFD)-induced obesity. Importantly, FLCN ablation leads to chronic hyperactivation of AMPK, which in turns induces and activates two key transcriptional regulators of cellular metabolism, proliferator-activated receptor γ (PPARγ) coactivator-1α (PGC-1α) and estrogen-related receptor α (ERRα). Together, the AMPK/PGC-1α/ERRα molecular axis positively modulates the expression of metabolic genes to promote mitochondrial biogenesis and activity. In addition, mitochondrial uncoupling proteins as well as other markers of brown fat are up-regulated in both white and brown FLCN-null adipose tissues, underlying the increased resistance of Adipoq-FLCN knockout mice to cold exposure. These findings identify a key role of FLCN as a negative regulator of mitochondrial function and identify a novel molecular pathway involved in the browning of white adipocytes and the activity of brown fat.

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Fnip1 regulates skeletal muscle fiber type specification, fatigue resistance, and susceptibility to muscular dystrophy

Cited by 97 publications

References 45 publications

Mutation of Fnip1 is associated with B-cell deficiency, cardiomyopathy, and elevated AMPK activity

Mutation of Fnip1 is associated with B-cell deficiency, cardiomyopathy, and elevated AMPK activity

Chimpanzee super strength and human skeletal muscle evolution

Chronic AMPK activation via loss of FLCN induces functional beige adipose tissue through PGC-1α/ERRα

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