Quantitative analysis of neonatal skeletal muscle functional improvement in the mouse

Gokhin, David S.; Ward, Samuel R.; Bremner, Shannon N.; Lieber, Richard L.

doi:10.1242/jeb.014340

Cited by 102 publications

(106 citation statements)

References 27 publications

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“…1A). The isometric stress produced by the WT GAS increased from 26.8 Ϯ 2.0 kPa at P1 to 58.1 Ϯ 3.9 kPa at P7, consistent with a previous report (8) of intrinsic enhancement of skeletal muscle function during the postnatal development of mouse muscle. The NEB-KO GAS generated only 19.5 Ϯ 2.0 kPa at P1, which was 27% less than the WT GAS (P Ͻ 0.05), and this value deteriorated to just 4.5 Ϯ 1.3 kPa at P7, which was 92% less than the age-matched WT GAS (P Ͻ 0.0001).…”

Section: Evidence For Functional and Structural Muscle Degenerationsupporting

confidence: 91%

“…Due to the relatively low myofibrillar packing in neonatal mouse muscle (8), laser transillumination did not provide a clear diffraction pattern for measuring average GAS sarcomere length (L s) when muscles were in the testing chamber. Instead, a separate set of measurements was performed using 1-dayold WT and NEB-KO hindlimbs that had been immersion fixed overnight in 3.7% formaldehyde with knee and ankle angles set at 90°u sing anodized steel minutien pins through the foot and femur, respectively, corresponding to a "neutral" joint configuration.…”

Section: Methodsmentioning

confidence: 99%

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Reduced thin filament length in nebulin-knockout skeletal muscle alters isometric contractile properties

Gokhin

Bang

Zhang

et al. 2009

American Journal of Physiology-Cell Physiology

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Gokhin DS, Bang ML, Zhang J, Chen J, Lieber RL. Reduced thin filament length in nebulin-knockout skeletal muscle alters isometric contractile properties. Am J Physiol Cell Physiol 296: C1123-C1132, 2009. First published March 18, 2009 doi:10.1152/ajpcell.00503.2008 is a large, rod-like protein believed to dictate actin thin filament length in skeletal muscle. NEB gene defects are associated with congenital nemaline myopathy. The functional role of NEB was investigated in gastrocnemius muscles from neonatal wild-type (WT) and NEB knockout (NEB-KO) mice, whose thin filaments have uniformly shorter lengths compared with WT mice. Isometric stress production in NEB-KO skeletal muscle was reduced by 27% compared with WT skeletal muscle on postnatal day 1 and by 92% on postnatal day 7, consistent with functionally severe myopathy. NEB-KO muscle was also more susceptible to a decline in stress production during a bout of 10 cyclic isometric tetani. Length-tension properties in NEB-KO muscle were altered in a manner consistent with reduced thin filament length, with length-tension curves from NEB-KO muscle demonstrating a 7.4% narrower functional range and an optimal length reduced by 0.13 muscle lengths. Expression patterns of myosin heavy chain isoforms and total myosin content did not account for the functional differences between WT and NEB-KO muscle. These data indicate that NEB is essential for active stress production, maintenance of functional integrity during cyclic activation, and lengthtension properties consistent with a role in specifying normal thin filament length. Continued analysis of NEB's functional properties will strengthen the understanding of force transmission and thin filament length regulation in skeletal muscle and may provide insights into the molecular processes that give rise to nemaline myopathy. neonatal mouse; isometric stress; myosin heavy chain; length-tension curve FORCE GENERATION in skeletal muscle results from the interdigitation of actin (thin) filaments and myosin (thick) filaments in the sarcomeres of the myofibrillar lattice. The magnitude of active force production is predicted by the sliding filament model, which states that active muscle force is proportional to the degree of thin and thick filament overlap (15, 16). The length-tension relationship quantifies the relationship between myofilament overlap and force production and is determined by eliciting isometric tetani at a discrete series of lengths (7,9,10,14). Myofilaments are polymeric, but their lengths are controlled precisely during sarcomere assembly and are highly uniform within a fiber (6, 24). Myofilament length varies across muscle type and species (11,13,43,44,47), with resultant functional consequences on the shape of the lengthtension curve (11). Therefore, the molecular basis of myofilament length regulation has substantial physiological implications.Previous studies have demonstrated that thin filament length is partly controlled by the action of "capping" proteins. At the thin filament barbed end (anchore...

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Section: Evidence For Functional and Structural Muscle Degenerationsupporting

confidence: 91%

Section: Methodsmentioning

confidence: 99%

Reduced thin filament length in nebulin-knockout skeletal muscle alters isometric contractile properties

Gokhin

Bang

Zhang

et al. 2009

American Journal of Physiology-Cell Physiology

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“…In the first 3 weeks of life, muscle mass accumulates rapidly through the accretion of myonuclei from activated muscle satellite cells in the mouse (46,47). Despite their small size, Atrx cKO mice had normal numbers of resident satellite cells that were capable of activating and entering a proliferative phase.…”

Section: Discussionmentioning

confidence: 99%

Compromised genomic integrity impedes muscle growth after Atrx inactivation

Huh¹,

O’Dea²,

Ouazia³

et al. 2012

J. Clin. Invest.

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ATR-X syndrome is a severe intellectual disability disorder caused by mutations in the ATRX gene. Many ancillary clinical features are attributed to CNS deficiencies, yet most patients have muscle hypotonia, delayed ambulation, or kyphosis, pointing to an underlying skeletal muscle defect. Here, we identified a cell-intrinsic requirement for Atrx in postnatal muscle growth and regeneration in mice. Mice with skeletal muscle-specific Atrx conditional knockout (Atrx cKO mice) were viable, but by 3 weeks of age presented hallmarks of underdeveloped musculature, including kyphosis, 20% reduction in body mass, and 34% reduction in muscle fiber caliber. Atrx cKO mice also demonstrated a marked regeneration deficit that was not due to fewer resident satellite cells or their inability to terminally differentiate. However, activation of Atrx-null satellite cells from isolated muscle fibers resulted in a 9-fold reduction in myoblast expansion, caused by delayed progression through mid to late S phase. While in S phase, Atrx colocalized specifically to late-replicating chromatin, and its loss resulted in rampant signs of genomic instability. These observations support a model in which Atrx maintains chromatin integrity during the rapid developmental growth of a tissue.

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“…Between E17.5 and P6, long bones increased in length ~3-fold ( Fig. 1B) and muscles attached to them increased their mass and consequently their forcegenerating potential (Gokhin et al, 2008) ~5-fold (Fig. 1C).…”

Section: Developing Bones Are Exposed To Increasing Mechanical Stressesmentioning

confidence: 99%

Muscle force regulates bone shaping for optimal load-bearing capacity during embryogenesis

et al. 2011

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SUMMARYThe vertebrate skeleton consists of over 200 individual bones, each with its own unique shape, size and function. We study the role of intrauterine muscle-induced mechanical loads in determining the three-dimensional morphology of developing bones. Analysis of the force-generating capacity of intrauterine muscles in mice revealed that developing bones are subjected to significant and progressively increasing mechanical challenges. To evaluate the effect of intrauterine loads on bone morphogenesis and the contribution of the emerging shape to the ability of bones to withstand these loads, we monitored structural and mineral changes during development. Using daily micro-CT scans of appendicular long bones we identify a developmental program, which we term preferential bone growth, that determines the specific circumferential shape of each bone by employing asymmetric mineral deposition and transient cortical thickening. Finite element analysis demonstrates that the resulting bone structure has optimal load-bearing capacity. To test the hypothesis that muscle forces regulate preferential bone growth in utero, we examine this process in a mouse strain (mdg) that lacks muscle contractions. In the absence of mechanical loads, the stereotypical circumferential outline of each bone is lost, leading to the development of mechanically inferior bones. This study identifies muscle force regulation of preferential bone growth as the module that shapes the circumferential outline of bones and, consequently, optimizes their load-bearing capacity during development. Our findings invoke a common mechanism that permits the formation of different circumferential outlines in different bones.

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Quantitative analysis of neonatal skeletal muscle functional improvement in the mouse

Cited by 102 publications

References 27 publications

Reduced thin filament length in nebulin-knockout skeletal muscle alters isometric contractile properties

Reduced thin filament length in nebulin-knockout skeletal muscle alters isometric contractile properties

Compromised genomic integrity impedes muscle growth after Atrx inactivation

Muscle force regulates bone shaping for optimal load-bearing capacity during embryogenesis

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