SERCA1 overexpression minimizes skeletal muscle damage in dystrophic mouse models

Mázala, Davi A. G.; Pratt, Stephen J.; Chen, Dapeng; Molkentin, Jeffery D.; Lovering, Richard M.; Chin, Eva R.

doi:10.1152/ajpcell.00341.2014

Cited by 55 publications

(61 citation statements)

References 81 publications

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“…H). Because of the difference in maximal relaxation rates and overexpression of SERCA1 in mdx muscle provides protection from ECC‐induced force loss , we measured SERCA1 expression in EDL, PL, and Sol muscle. Sol muscle expressed SERCA1 to 60% of EDL and PL levels (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Utrophin content is another factor possibly explaining Sol insensitivity to ECC because it has elevated levels of utrophin and overexpression of either full‐length or truncated utrophin can restore mechanical properties of dystrophin‐deficient muscle and ameliorate the majority of skeletal muscle phenotypes, including sensitivity to ECC . There is also evidence that changes in cytosolic calcium can impact ECC‐induced force loss and that overexpression of SERCA1 provides protection . Finally, we and others have previously shown that skeletal muscles in mdx mice have 10‐ and 14‐fold greater expression of cytoplasmic γ‐ and β‐actins than wild‐type mice, respectively, while transgenic overexpression of either actin isoform significantly protects the EDL from ECC‐induced force loss .…”

Section: Introductionmentioning

confidence: 86%

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Variable cytoplasmic actin expression impacts the sensitivity of different dystrophin‐deficient mdx skeletal muscles to eccentric contraction

et al. 2019

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Eccentric contractions (ECCs) induce force loss in several skeletal muscles of dystrophin‐deficient mice (mdx), with the exception of the soleus (Sol). The eccentric force : isometric force (ECC : ISO), expression level of utrophin, fiber type distribution, and sarcoendoplasmic reticulum calcium ATPase expression are factors that differ between muscles and may contribute to the sensitivity of mdx skeletal muscle to ECC. Here, we confirm that the Sol of mdx mice loses only 13% force compared to 87% in the extensor digitorum longus (EDL) following 10 ECC of isolated muscles. The Sol has a greater proportion of fibers expressing Type I myosin heavy chain (MHC) and expresses 2.3‐fold more utrophin compared to the EDL. To examine the effect of ECC : ISO, we show that the mdx Sol is insensitive to ECC at ECC : ISO up to 230 ± 15%. We show that the peroneus longus (PL) muscle presents with similar ECC : ISO compared to the EDL, intermediate force loss (68%) following 10 ECC, and intermediate fiber type distribution and utrophin expression relative to EDL and Sol. The combined absence of utrophin and dystrophin in mdx/utrophin−/− mice rendered the Sol only partially susceptible to ECC and exacerbated force loss in the EDL and PL. Most interestingly, the expression levels of cytoplasmic β‐ and γ‐actins correlate inversely with a given muscle's sensitivity to ECC; EDL < PL < Sol. Our data indicate that fiber type, utrophin, and cytoplasmic actin expression all contribute to the differential sensitivities of mdxEDL, PL, and Sol muscles to ECC.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 86%

Variable cytoplasmic actin expression impacts the sensitivity of different dystrophin‐deficient mdx skeletal muscles to eccentric contraction

et al. 2019

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“…FDB muscle fibers from wildtype or transgenic mice have been previously used in numerous studies to investigate the effect of genetic mutations or aging on e.g. calcium dynamics, reactive oxygen production and mitochondrial function (23)(24)(25). FDB fibers are fully differentiated and maximally contractile already in newborn mice, and all secondary developmental processes such as the formation of the tethering structures for the sarcoplasmic reticulum and mitochondria are completed by the age of 8 weeks (26).…”

Section: Discussionmentioning

confidence: 99%

Measurement of skeletal muscle fiber contractility with high-speed traction microscopy

Rausch

Böhringer

Steinmann

et al. 2019

Preprint

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We describe a technique for simultaneous quantification of the contractile forces and cytosolic calcium dynamics of muscle fibers embedded in three-dimensional biopolymer gels. We derive a scaling law for linear elastic matrices such as basement membrane extract hydrogels (Matrigel) that allows us to measure contractile force from the shape of the relaxed and contracted muscle cell and the Young's modulus of the matrix, without further knowledge of the matrix deformations surrounding the cell and without performing computationally intensive inverse force reconstruction algorithms. We apply our method to isolated mouse flexor digitorum brevis (FDB) fibers that are embedded in 10 mg/ml Matrigel. Upon electrical stimulation, individual FDB fibers show twitch forces of 0.37 µN ± 0.15 µN and tetanic forces (100 Hz stimulation frequency) of 2.38 µN ± 0.71 µN, corresponding to a tension of 0.44 kPa ± 0.25 kPa and 2.53 kPa ± 1.17 kPa, respectively. Contractile forces of FDB fibers increase in response to caffeine and the troponin-calcium-stabilizer Tirasemtiv, similar to responses measured in whole muscle.From simultaneous high-speed measurements of cell length changes and cytosolic calcium concentration using confocal line scanning at a frequency of 2048 Hz, we show that twitch and tetanic force responses to electric pulses follow the low-pass filtered calcium signal. In summary, we present a technically simple high speed and high throughput method for measuring contractile forces and cytosolic calcium dynamics of single muscle fibers. We expect that our method will help to reduce preparation time, costs, and the number of sacrificed animals needed for experiments such as drug testing. Statement of significanceWe describe a high speed, high throughput method for the simultaneous measurement of contractile force and cytoplasmic calcium dynamics following electrical pulse stimulation of muscle fibers embedded in a 3-dimensional biopolymer matrix. In contrast to the classical approach of attaching muscle fibers to a force-transducer, our method allows for a highly efficient, parallel analysis of large numbers of fibers under different treatment conditions.

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“…Indeed, inhibiting Ca 2ϩ leak from RyR1 (1), and preventing an intracellular Ca 2ϩ influx (8, 9), were both successful in rescuing some of the phenotypic changes in muscles of dystrophic mice. Thus, increased SERCA overexpression as shown by Mázala et al (7) and others (4) appears to be beneficial in disease conditions in which there is a continuous elevation of [Ca 2ϩ ] i (Fig. 1).…”

mentioning

confidence: 52%

Can't live with or without it: calcium and its role in Duchenne muscular dystrophy-induced muscle weakness. Focus on “SERCA1 overexpression minimizes skeletal muscle damage in dystrophic mouse models”

Cheng

Andersson

Lanner

2015

American Journal of Physiology-Cell Physiology

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DUCHENNE MUSCULAR DYSTROPHY (DMD) is an X-linked genetic disorder caused by the lack of the membrane-associated protein, dystrophin, which leads to premature death (5). The absence of dystrophin increases susceptibility of fibers to muscle damage. Repeated myofiber damage results in ineffective muscle repair and development of pseudo-hypertrophied muscles that are weak for their given size and mass. As of yet, the mechanisms underlying the functional impairment in dystrophic muscle have not been completely elucidated. However, recent evidence points to elevated intracellular Ca 2ϩ homeostasis being a cause or facilitator to the development of muscle weakness in muscular dystrophies (1,4,8,9). Ca 2ϩ is the major regulator of muscle force generation in skeletal muscle. At the muscle level, an action potential propagating along the sarcolemma traverses down the transverse tubules where the voltage-sensing dihydropyridine receptor mechanically interacts with ryanodine receptor 1 (RyR1) to release Ca 2ϩ from its main storage site, the sarcoplasmic reticulum (SR). Micromolar concentrations of Ca 2ϩ released from the SR into the myoplasm enable actin and myosin interaction, which generates contractile force. Then, reuptake of Ca 2ϩ into the SR by SR Ca 2ϩ -ATPase (SERCA) allows the muscle fiber to relax. Although strict control of intracellular Ca 2ϩ homeostasis is critical for controlling muscle contraction and relaxation, Ca 2ϩ is an equally important secondary messenger that triggers muscle adaptation or degradation (6). In rested noncontracting muscle, small elevations in nanomolar concentrations of myoplasmic Ca 2ϩ ([Ca 2ϩ ] i ) can induce beneficial muscle adaptations including upregulation of muscle thermogenesis (2), and increased mitochondrial biogenesis and fatigue resistance (3). However, larger elevations in [Ca 2ϩ ] i in the hundred nanomolar range can be deleterious to muscle function (8, 9). Indeed, elevated [Ca 2ϩ ] i is evident in muscles of dystrophic mice, whereby excessive Ca 2ϩ accumulation increases calpain activation (4), impairs autophagy (8), and can increase mitochondrial Ca 2ϩ accumulation (4). Since SERCA controls the removal of Ca 2ϩ from the myoplasm and back into the SR, the article by Mázala and colleagues (7) investigated whether SERCA1 overexpression in fast-twitch muscle fibers of mdx mice could rescue the pseudohypertrophy and weakness that develops as a result of elevated [Ca 2ϩ ] i . Mázala and colleagues used two different mouse ]i) in rested fibers of dystrophic muscle. Elevated [Ca 2ϩ ]i appears to depend on reactive oxygen species (ROS) production and potentially involves increased Ca 2ϩ influx through the sarcolemma (1), and increased Ca 2ϩ leak through the ryanodine receptor (RyR1) (2). Increased sarcoplasmic reticulum Ca 2ϩ -ATPase (SERCA) overexpression (3) decreases [Ca 2ϩ ]i and reduces the pseudo-hypertrophy common to dystrophic muscle. It is not known how decreased [Ca 2ϩ ]i reduces pseudo-hypertrophy and reverses the phenotype in dystrophic mice (4). ...

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SERCA1 overexpression minimizes skeletal muscle damage in dystrophic mouse models

Cited by 55 publications

References 81 publications

Variable cytoplasmic actin expression impacts the sensitivity of different dystrophin‐deficient mdx skeletal muscles to eccentric contraction

Variable cytoplasmic actin expression impacts the sensitivity of different dystrophin‐deficient mdx skeletal muscles to eccentric contraction

Measurement of skeletal muscle fiber contractility with high-speed traction microscopy

Can't live with or without it: calcium and its role in Duchenne muscular dystrophy-induced muscle weakness. Focus on “SERCA1 overexpression minimizes skeletal muscle damage in dystrophic mouse models”

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