Mouse transgenic lines that selectively label type I, type IIa, and types IIX+B skeletal muscle fibers

Chakkalakal, Joe V.; Kuang, Shihuan; Buffelli, Mario Rosario; Lichtman, Jeff W.; Sanes, Joshua R.

doi:10.1002/dvg.20794

Cited by 21 publications

(28 citation statements)

References 29 publications

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“…Because each muscle contains a mixture of distinct fiber types, we utilized transgenic mouse models that allow fluorescent labeling of type I, IIA and IIX/IIB fibers (see Experimental Procedures) (Chakkalakal et al, 2012b). As expected, the majority of EDL fibers were identified as glycolytic type IIX/IIB, and these have punctate mitochondria (Figure 1D, 1E, 1F, and S1A).…”

Section: Resultsmentioning

confidence: 99%

Mitochondrial Dynamics Is a Distinguishing Feature of Skeletal Muscle Fiber Types and Regulates Organellar Compartmentalization

et al. 2015

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SUMMARY Skeletal muscle fibers differentiate into specific fiber types with distinct metabolic properties determined by their reliance on oxidative phosphorylation (OXPHOS). Using in vivo approaches, we find that OXPHOS-dependent fibers, compared to glycolytic fibers, contain elongated mitochondrial networks with higher fusion rates that are dependent on the mitofusins Mfn1 and Mfn2. Switching of a glycolytic fiber to an oxidative IIA type is associated with elongation of mitochondria, suggesting that mitochondrial fusion is linked to metabolic state. Furthermore, we reveal that mitochondrial proteins are compartmentalized to discrete domains centered around their nuclei of origin. The domain dimensions are dependent on fiber type and are regulated by the mitochondrial dynamics proteins Mfn1, Mfn2, and Mff. Our results indicate that mitochondrial dynamics is tailored to fiber type physiology and provides a rationale for the segmental defects characteristic of aged and diseased muscle fibers.

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Section: Resultsmentioning

confidence: 99%

Mitochondrial Dynamics Is a Distinguishing Feature of Skeletal Muscle Fiber Types and Regulates Organellar Compartmentalization

et al. 2015

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“…Slow-twitch type I fibers use oxidative metabolism and express the slow MyHC isoform MyHC-I; in contrast, fast-twitch type II fibers present glycolytic or mixed metabolism and express three fast MyHC isoforms (MyHC-IIa, IIx/d, and IIb) (Peter et al., 1972, Schiaffino et al., 1988, Chakkalakal et al., 2012). The phenotype of post-natal muscle fibers is strictly regulated by extrinsic signals such as muscle activity and hormones (Butler-Browne et al., 1982, Gambke et al., 1983, Russell et al., 1988).…”

Section: Discussionmentioning

confidence: 99%

Nfix Induces a Switch in Sox6 Transcriptional Activity to Regulate MyHC-I Expression in Fetal Muscle

et al. 2016

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SummarySox6 belongs to the Sox gene family and plays a pivotal role in fiber type differentiation, suppressing transcription of slow-fiber-specific genes during fetal development. Here, we show that Sox6 plays opposite roles in MyHC-I regulation, acting as a positive and negative regulator of MyHC-I expression during embryonic and fetal myogenesis, respectively. During embryonic myogenesis, Sox6 positively regulates MyHC-I via transcriptional activation of Mef2C, whereas during fetal myogenesis, Sox6 requires and cooperates with the transcription factor Nfix in repressing MyHC-I expression. Mechanistically, Nfix is necessary for Sox6 binding to the MyHC-I promoter and thus for Sox6 repressive function, revealing a key role for Nfix in driving Sox6 activity. This feature is evolutionarily conserved, since the orthologs Nfixa and Sox6 contribute to repression of the slow-twitch phenotype in zebrafish embryos. These data demonstrate functional cooperation between Sox6 and Nfix in regulating MyHC-I expression during prenatal muscle development.

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“…One main criterion to classify myofiber types is based on the myosin heavy chain (Myh) isoform expression. In this scenario, fast myofibers can be further divided into type IIA, IIX and IIB based on the expression of Myh2, Myh1 and Myh4 genes, respectively (Chakkalakal et al, 2012). By contrast, type I slow myofibers uniquely express the Myh7 gene, encoding the β-myosin heavy chain protein that is also expressed in cardiac muscles (Chen and Wang, 2012).…”

Section: Introductionmentioning

confidence: 99%

Heterogeneous activation of a slow myosin gene in proliferating myoblasts and differentiated single myofibers

Wang

et al. 2015

Developmental Biology

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Each skeletal muscle contains a fixed ratio of fast and slow myofibers that are distributed in a stereotyped pattern to achieve a specific motor function. How myofibers are specified during development and regeneration is poorly understood. Here we address this question using transgenic reporter mice that indelibly mark the myofiber lineages based on activation of fast or slow myosin. Lineage tracing indicates that during development all muscles have activated the fast myosin gene Myl1, but not the slow myosin gene Myh7, which is activated in all slow but a subset of fast myofibers. Similarly, most nascent myofibers do not activate Myh7 during fast muscle regeneration, but the ratio and pattern of fast and slow myofibers are restored at the completion of regeneration. At the single myofiber level, most mature fast myofibers are heterogeneous in nuclear composition, manifested by mosaic activation of Myh7. Strikingly, Myh7 is activated in a subpopulation of proliferating myoblasts that co-express the myogenic progenitor marker Pax7. When induced to differentiate, the Myh7-activated myoblasts differentiate more readily than the non-activated myoblasts, and have a higher tendency, but not restricted, to become slow myotubes. Together, our data reveal significant nuclear heterogeneity within a single myofiber, and challenge the conventional view that myosin genes are only expressed after myogenic differentiation. These results provide novel insights into the regulation of muscle fiber type specification.

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Mouse transgenic lines that selectively label type I, type IIa, and types IIX+B skeletal muscle fibers

Cited by 21 publications

References 29 publications

Mitochondrial Dynamics Is a Distinguishing Feature of Skeletal Muscle Fiber Types and Regulates Organellar Compartmentalization

Mitochondrial Dynamics Is a Distinguishing Feature of Skeletal Muscle Fiber Types and Regulates Organellar Compartmentalization

Nfix Induces a Switch in Sox6 Transcriptional Activity to Regulate MyHC-I Expression in Fetal Muscle

Heterogeneous activation of a slow myosin gene in proliferating myoblasts and differentiated single myofibers

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