The Overlooked Role of Fiber Length in Mechanical Load-Induced Growth of Skeletal Muscle

Jorgenson, Kent W.; Hornberger, Troy A.

doi:10.1249/jes.0000000000000198

Cited by 26 publications

(23 citation statements)

References 5 publications

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“…The fact that the MUT rats were still able to increase muscle weight to a similar extent despite only mild hypertrophy and the absence of hyperplasia may point towards other coping mechanisms with loading, such as changes in connective tissue or muscle length. 64 For patients affected by an orthologous mutation, these data in conjunction with the results from above indicate that while an increase in muscle mass and cross-sectional area is possible when loading desminopathic muscle, caution should be used when therapists make decisions on the degree of loading. While still potentially useful in the prevention or slowing of muscle atrophy, the decreased ability to cope with very high loads and a higher susceptibility to muscle damage warrants a particularly careful approach to resistance exercise in these patients.…”

Section: Discussionmentioning

confidence: 83%

“…Together, these data indicate that MUT muscles have a decreased ability to grow and are unable to split or generate new smaller fibres in response to a supra‐physiological load. The fact that the MUT rats were still able to increase muscle weight to a similar extent despite only mild hypertrophy and the absence of hyperplasia may point towards other coping mechanisms with loading, such as changes in connective tissue or muscle length 64 . For patients affected by an orthologous mutation, these data in conjunction with the results from above indicate that while an increase in muscle mass and cross‐sectional area is possible when loading desminopathic muscle, caution should be used when therapists make decisions on the degree of loading.…”

Section: Discussionmentioning

confidence: 99%

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Generation of desminopathy in rats using CRISPR‐Cas9

Langer

Mossakowski

Willis

et al. 2020

J cachexia sarcopenia muscle

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Background Desminopathy is a clinically heterogeneous muscle disease caused by over 60 different mutations in desmin. The most common mutation with a clinical phenotype in humans is an exchange of arginine to proline at position 350 of desmin leading to p.R350P. We created the first CRISPR-Cas9 engineered rat model for a muscle disease by mirroring the R350P mutation in humans. Methods Using CRISPR-Cas9 technology, Des c.1045-1046 (AGG > CCG) was introduced into exon 6 of the rat genome causing p.R349P. The genotype of each animal was confirmed via quantitative PCR. Six male rats with a mutation in desmin (n = 6) between the age of 120-150 days and an equal number of wild type littermates (n = 6) were used for experiments. Maximal plantar flexion force was measured in vivo and combined with the collection of muscle weights, immunoblotting, and histological analysis. In addition to the baseline phenotyping, we performed a synergist ablation study in the same animals. Results We found a difference in the number of central nuclei between desmin mutants (1 ± 0.4%) and wild type littermates (0.2 ± 0.1%; P < 0.05). While muscle weights did not differ, we found the levels of many structural proteins to be altered in mutant animals. Dystrophin and syntrophin were increased 54% and 45% in desmin mutants, respectively (P < 0.05). Dysferlin and Annexin A2, proteins associated with membrane repair, were increased twofold and 32%, respectively, in mutants (P < 0.05). Synergist ablation caused similar increases in muscle weight between mutant and wild type animals, but changes in fibre diameter revealed that fibre hypertrophy in desmin mutants was hampered compared with wild type animals (P < 0.05). Conclusions We created a novel animal model for desminopathy that will be a useful tool in furthering our understanding of the disease. While mutant animals at an age corresponding to a preclinical age in humans show no macroscopic differences, microscopic and molecular changes are already present. Future studies should aim to further decipher those biological changes that precede the clinical progression of disease and test therapeutic approaches to delay disease progression.

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Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Generation of desminopathy in rats using CRISPR‐Cas9

Langer

Mossakowski

Willis

et al. 2020

J cachexia sarcopenia muscle

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“…The greater effect on fiber CSA in 1.5-month-old animals following castration may be a result of testosterone playing a role in mediating axial lengthening of the tibialis anterior myofibers. The causative relationship between muscle length and fiber CSA were recently highlighted by Jorgenson and Hornberger [ 35 ]. Additionally, testosterone administration is associated with increased addition of myoblasts [ 36 , 37 ], which is a key part of secondary fiber formation [ 38 ].…”

Section: Discussionmentioning

confidence: 99%

Maintenance of muscle mass in adult male mice is independent of testosterone

et al. 2021

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Testosterone is considered a potent anabolic agent in skeletal muscle with a well-established role in adolescent growth and development in males. However, the role of testosterone in the regulation of skeletal muscle mass and function throughout the lifespan has yet to be fully established. While some studies suggest that testosterone is important for the maintenance of skeletal muscle mass, an understanding of the role this hormone plays in young, adult, and old males with normal and low serum testosterone levels is lacking. We investigated the role testosterone plays in the maintenance of muscle mass by examining the effect of orchiectomy-induced testosterone depletion in C57Bl6 male mice at ages ranging from early postnatal through old age (1.5-, 5-, 12-, and 24-month old mice). Following 28 days of testosterone depletion, we assessed mass and fiber cross-sectional-area (CSA) of the tibialis anterior, gastrocnemius, and quadriceps muscles. In addition, we measured global rates of protein synthesis and degradation using the SuNSET method, western blots, and enzyme activity assays. Twenty-eight days of testosterone depletion resulted in reduced muscle mass in the two youngest cohorts, but had no effect in the two oldest cohorts. Mean CSA decreased only in the youngest cohort and only in the tibialis anterior muscle. Testosterone depletion resulted in a general increase in proteasome activity at all ages. No change in protein synthesis was detected at the terminal time point. These data suggest that within physiological serum concentrations, testosterone may not be critical for the maintenance of muscle mass in mature male mice; however, in young mice testosterone is crucial for normal growth.

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“…Upon first consideration, it can be challenging to appreciate how both longitudinal and radial growth of fascicles can lead to an increase in whole muscle CSA. Thus, to visualize these points, we have taken advantage of a geometric model that can be used to predict changes in the architectural properties of skeletal muscle [ 75 , 76 ]. Specifically, as shown in Figure 3 , we used this model to illustrate how changes in either fascicle length (Lf), or fascicle diameter (Df), could produce a 30% increase in whole muscle CSA (the upper end of what is typically observed in humans after 8–16 weeks of resistance exercise).…”

Section: Mechanical Load-induced Growth Of Skeletal Muscle At the mentioning

confidence: 99%

Identifying the Structural Adaptations that Drive the Mechanical Load-Induced Growth of Skeletal Muscle: A Scoping Review

Jorgenson

Phillips

Hornberger

2020

Cells

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The maintenance of skeletal muscle mass plays a critical role in health and quality of life. One of the most potent regulators of skeletal muscle mass is mechanical loading, and numerous studies have led to a reasonably clear understanding of the macroscopic and microscopic changes that occur when the mechanical environment is altered. For instance, an increase in mechanical loading induces a growth response that is mediated, at least in part, by an increase in the cross-sectional area of the myofibers (i.e., myofiber hypertrophy). However, very little is known about the ultrastructural adaptations that drive this response. Even the most basic questions, such as whether mechanical load-induced myofiber hypertrophy is mediated by an increase in the size of the pre-existing myofibrils and/or an increase in the number myofibrils, have not been resolved. In this review, we thoroughly summarize what is currently known about the macroscopic, microscopic and ultrastructural changes that drive mechanical load-induced growth and highlight the critical gaps in knowledge that need to be filled.

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The Overlooked Role of Fiber Length in Mechanical Load-Induced Growth of Skeletal Muscle

Cited by 26 publications

References 5 publications

Generation of desminopathy in rats using CRISPR‐Cas9

Generation of desminopathy in rats using CRISPR‐Cas9

Maintenance of muscle mass in adult male mice is independent of testosterone

Identifying the Structural Adaptations that Drive the Mechanical Load-Induced Growth of Skeletal Muscle: A Scoping Review

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