Axon and muscle spindle hyperplasia in the myostatin null mouse

Elashry, Mohamed I.; Otto, Anthony; Matsakas, Antonios; El-Morsy, Salah E.; Jones, Lee; Anderson, Bethan; Patel, Ketan

doi:10.1111/j.1469-7580.2010.01327.x

Cited by 13 publications

(18 citation statements)

References 34 publications

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“…) and 34% increase in spindle counts (mean of 26 and 41%; Elashry et al. ) in the myostatin null mouse are consistent with this relationship (2 0.33 = 1.257). It is interesting, therefore, that in the within‐species analysis of the six strains of mice the same relationship is not found between soleus muscles differing in mass by up to an order of magnitude.…”

Section: Discussionmentioning

confidence: 55%

“…; Elashry et al. ). The finding in the present study, that BEL strain has ≈40% more spindles than the LG/J strain, provides evidence that naturally occurring genetic variability also influences the abundance of these proprioceptors.…”

Section: Discussionmentioning

confidence: 98%

“…In contrast, the phenotypic differences between strains are largely attributable to genetic differences, which range from hundreds of thousands of single nucleotide polymorphisms (SNP; Frazer et al 2007) to larger structural variations of the genomes of different strains (Yalcin et al 2012). Previous studies using the gene knockout approach demonstrated that abundance of muscle spindles can be affected by a variety of factors, particularly growth and trophic factor signalling, including ErbB2, NT-3 and myostatin (Ernfors et al 1994;Andrechek et al 2002;Elashry et al 2011). The finding in the present study, that BEL strain has %40% more spindles than the LG/J strain, provides evidence Fig.…”

Section: Effects Of Genetic Variantsmentioning

confidence: 99%

“…), increased both muscle size and spindle number (Elashry et al. ). Thus, genetic factors can substantially affect the number of spindles, not merely their presence or absence, and can do so sometimes in concert with extrafusal muscle properties.…”

Section: Introductionmentioning

confidence: 99%

“…Gene knockout models have shown that disruption of Erbb2 (Andrechek et al 2002) or the NT-3 coding gene, Ntf3, (Ernfors et al 1994) in muscle led to the early degeneration or complete absence of spindles, with reduced numbers of spindles in heterozygotes. Conversely the disruption of the myostatin gene, a known suppressor of muscle growth (McPherron et al 1997), increased both muscle size and spindle number (Elashry et al 2011). Thus, genetic factors can substantially affect the number of spindles, not merely their presence or absence, and can do so sometimes in concert with extrafusal muscle properties.…”

Section: Introductionmentioning

confidence: 99%

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Analyses of muscle spindles in the soleus of six inbred mouse strains

Lionikas

Smith

et al. 2013

Journal of Anatomy

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Adult muscle size and fibre-type composition are heritable traits that vary substantially between individuals. We used inbred mouse strains in which soleus muscle mass varied by an order of magnitude to explore whether properties of muscle spindles can also be influenced by genetic factors. Skip-serial cross-sections of soleus muscles dissected from 15 male mice of BEH, BEL, C57BL/6J, DUH, LG/J and SM/J strains were analysed for number of muscle spindles and characteristics of intrafusal and extrafusal fibres following ATPase staining. The BEL and DUH strains determined the range of: soleus mean size, a 10-fold difference from 2.1 to 22.3 mg, respectively; the mean number of extrafusal fibres, a 2.5-fold difference from 497 to 1249; and mean fibrecross-sectional area, three-fold difference, e.g. for type 1 fibres, from 678 to 1948 lm 2 . The range of mean proportion of type 1 fibres was determined by C57BL/6J (31%) and DUH (64%) strains. The mean number of spindles per muscle ranged between nine (LG/J) and 13 (BEL) (strain effect P < 0.02). Genetic correlations between spindle count and muscle weight or properties of extrafusal fibres were weak and not statistically significant. However, there was a strong correlation between the proportion of spindles with more than one bag 2 fibre and the proportion of extrafusal fibres that were of type 1, and strain-dependent variation in the numbers of such spindles was statistically significant. The numbers of intrafusal fibres per spindle ranged from 2 to 8, with the most common complement of four found in 75.6% of spindles. There were no significant differences between the strains in the mean numbers of intrafusal fibres; however, the variance of the number was significantly less for the C57BL/6J strain than for any of the others. We conclude that abundance of muscle spindles and their intrafusal-fibre composition are substantially determined by genetic factors, which are different from those affecting muscle size and properties of the extrafusal fibres.

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Section: Discussionmentioning

confidence: 55%

Section: Discussionmentioning

confidence: 98%

Section: Effects Of Genetic Variantsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Analyses of muscle spindles in the soleus of six inbred mouse strains

Lionikas

Smith

et al. 2013

Journal of Anatomy

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Myostatin inhibition in combination with antisense oligonucleotide therapy improves outcomes in spinal muscular atrophy

Zhou

Meng

Malerba

et al. 2020

J cachexia sarcopenia muscle

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Background Spinal muscular atrophy (SMA) is caused by genetic defects in the survival motor neuron 1 (SMN1) gene that lead to SMN deficiency. Different SMN‐restoring therapies substantially prolong survival and function in transgenic mice of SMA. However, these therapies do not entirely prevent muscle atrophy and restore function completely. To further improve the outcome, we explored the potential of a combinatorial therapy by modulating SMN production and muscle‐enhancing approach as a novel therapeutic strategy for SMA. Methods The experiments were performed in a mouse model of severe SMA. A previously reported 25‐mer morpholino antisense oligomer PMO25 was used to restore SMN expression. The adeno‐associated virus‐mediated expression of myostatin propeptide was used to block the myostatin pathway. Newborn SMA mice were treated with a single subcutaneous injection of 40 μg/g (therapeutic dose) or 10 μg/g (low‐dose) PMO25 on its own or together with systemic delivery of a single dose of adeno‐associated virus‐mediated expression of myostatin propeptide. The multiple effects of myostatin inhibition on survival, skeletal muscle phenotype, motor function, neuromuscular junction maturation, and proprioceptive afferences were evaluated. Results We show that myostatin inhibition acts synergistically with SMN‐restoring antisense therapy in SMA mice treated with the higher therapeutic dose PMO25 (40 μg/g), by increasing not only body weight (21% increase in male mice at Day 40), muscle mass (38% increase), and fibre size (35% increase in tibialis anterior muscle in 3 month female SMA mice), but also motor function and physical performance as measured in hanging wire test (two‐fold increase in time score) and treadmill exercise test (two‐fold increase in running distance). In SMA mice treated with low‐dose PMO25 (10 μg/g), the early application of myostatin inhibition prolongs survival (40% increase), improves neuromuscular junction maturation (50% increase) and innervation (30% increase), and increases both the size of sensory neurons in dorsal root ganglia (60% increase) and the preservation of proprioceptive synapses in the spinal cord (30% increase). Conclusions These data suggest that myostatin inhibition, in addition to the well‐known effect on muscle mass, can also positively influence the sensory neural circuits that may enhance motor neurons function. While the availability of the antisense drug Spinraza for SMA and other SMN‐enhancing therapies has provided unprecedented improvement in SMA patients, there are still unmet needs in these patients. Our study provides further rationale for considering myostatin inhibitors as a therapeutic intervention in SMA patients, in combination with SMN‐restoring drugs.

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Differential effects of myostatin deficiency on motor and sensory axons

et al. 2017

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Introduction Deletion of myostatin in mice (MSTN−/−) alters structural properties of peripheral axons. However, properties like axon diameter and myelin thickness were analyzed in mixed nerves, so it is unclear if loss of myostatin affects motor, sensory or both types of axons. Methods Using the MSTN−/− mouse model, we analyzed the effects of increasing the number of muscle fibers on axon diameter, myelin thickness, and internode length in motor and sensory axons. Results Axon diameter and myelin thickness were increased in motor axons of MSTN−/− mice without affecting internode length or axon number. The number of sensory axons was increased without affecting their structural properties. Discussion These results suggest that motor and sensory axons establish structural properties by independent mechanisms. Moreover, in motor axons, instructive cues from the neuromuscular junction may play a role in co-regulating axon diameter and myelin thickness, while internode length is established independently.

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Axon and muscle spindle hyperplasia in the myostatin null mouse

Cited by 13 publications

References 34 publications

Analyses of muscle spindles in the soleus of six inbred mouse strains

Analyses of muscle spindles in the soleus of six inbred mouse strains

Myostatin inhibition in combination with antisense oligonucleotide therapy improves outcomes in spinal muscular atrophy

Differential effects of myostatin deficiency on motor and sensory axons

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