Removal of MuRF1 Increases Muscle Mass in Nemaline Myopathy Models, but Does Not Provide Functional Benefits

Lindqvist, Johan; Kolb, Justin; Winter, J. de; Tonino, Paola; Hourani, Zaynab; Labeit, Siegfried; Ottenheijm, Coen A.C.; Granzier, Henk

doi:10.3390/ijms23158113

Cited by 3 publications

(4 citation statements)

References 63 publications

(103 reference statements)

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“…No change in myostatin was observed in a mouse model of mild actin-based NM. Additionally, myostatin positively regulates the expression of MuRF1 and MAFbx [16,26] and last year, we found that MuRF1 protein levels are elevated in a limited number of patients and two animal models of NEM2 [48]. Collectively, current data from animal experiments and clinical trials indicate that myostatin inhibition increases muscle size in animals and humans, but improvements in muscle function are diseasedependent [49].…”

Section: Discussionmentioning

confidence: 69%

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Pharmacological Inhibition of Myostatin in a Mouse Model of Typical Nemaline Myopathy Increases Muscle Size and Force

Lindqvist,

Granzier

2023

IJMS

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Nemaline myopathy is one of the most common non-dystrophic congenital myopathies. Individuals affected by this condition experience muscle weakness and muscle smallness, often requiring supportive measures like wheelchairs or respiratory support. A significant proportion of patients, approximately one-third, exhibit compound heterozygous nebulin mutations, which usually give rise to the typical form of the disease. Currently, there are no approved treatments available for nemaline myopathy. Our research explored the modulation of myostatin, a negative regulator of muscle mass, in combating the muscle smallness associated with the disease. To investigate the effect of myostatin inhibition, we employed a mouse model with compound heterozygous nebulin mutations that mimic the typical form of the disease. The mice were treated with mRK35, a myostatin antibody, through weekly intraperitoneal injections of 10 mg/kg mRK35, commencing at two weeks of age and continuing until the mice reached four months of age. The treatment resulted in an increase in body weight and an approximate 20% muscle weight gain across most skeletal muscles, without affecting the heart. The minimum Feret diameter of type IIA and IIB fibers exhibited an increase in compound heterozygous mice, while only type IIB fibers demonstrated an increase in wild-type mice. In vitro mechanical experiments conducted on intact extensor digitorum longus muscle revealed that mRK35 augmented the physiological cross-sectional area of muscle fibers and enhanced absolute tetanic force in both wild-type and compound heterozygous mice. Furthermore, mRK35 administration improved grip strength in treated mice. Collectively, these findings indicate that inhibiting myostatin can mitigate the muscle deficits in nebulin-based typical nemaline myopathy, potentially serving as a much-needed therapeutic option.

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Section: Discussionmentioning

confidence: 69%

“…Previous studies [20,24,48] have provided detailed descriptions of the intact muscle mechanic experiments. In brief, extensor digitorum longus (EDL) muscles were rapidly excised, and silk suture loops (USP 4-0) were tied to each tendon.…”

Section: Intact Muscle Mechanicsmentioning

confidence: 99%

Pharmacological Inhibition of Myostatin in a Mouse Model of Typical Nemaline Myopathy Increases Muscle Size and Force

Lindqvist,

Granzier

2023

IJMS

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“…[26][27][28][29][30][31] It has also been implicated in the regulation of thin filament length (TFL), as reduced levels of nebulin protein have been associated with shortened TFL in patients with NEB-related nemaline myopathy, as well as in nebulin-deficient mouse models, zebrafish, and chick skeletal myocytes. 30,[32][33][34][35][36][37][38][39] Despite investigating a number of therapeutic interventions including troponin activators such as Levosimendan, 40 CK-20066260, 30 dietary supplements 41 and myostatin inhibitors, 42,43 there are currently no effective therapies targeting the underlying pathological mechanisms for nebulinbased NEM (NEM2). It has been shown that Omecamtiv mecarbil (OM), a selective smallmolecule activator of cardiac myosin (MYH7) that was initially developed as a treatment for heart failure, 44,45 , increases submaximal force production in type I skeletal muscles of Neb cKO mouse model 46 and rat diaphragm.…”

Section: Introductionmentioning

confidence: 99%

“…Despite investigating a number of therapeutic interventions including troponin activators such as Levosimendan, 40 CK-20066260, 30 dietary supplements 41 and myostatin inhibitors, 42,43 there are currently no effective therapies targeting the underlying pathological mechanisms for nebulin-based NEM (NEM2). It has been shown that Omecamtiv mecarbil (OM), a selective small-molecule activator of cardiac myosin ( MYH7) that was initially developed as a treatment for heart failure, 44,45 , increases submaximal force production in type I skeletal muscles of Neb cKO mouse model 46 and rat diaphragm.…”

Section: Introductionmentioning

confidence: 99%

Characterization ofNEBmutations in patients reveals novel nemaline myopathy disease mechanisms and omecamtiv mecarbil force effects

Karimi,

van der Borgh,

Lindqvist

et al. 2023

Preprint

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Nebulin, a critical protein of the skeletal muscle thin filament, plays important roles in physiological processes such as regulating thin filament length (TFL), cross-bridge cycling, and myofibril alignment. Mutations in the nebulin gene (NEB) cause NEB-based nemaline myopathy (NEM2), a genetically heterogeneous disorder characterized by hypotonia and muscle weakness, currently lacking therapies targeting the underlying pathological mechanisms. In this study, we examined a cohort of ten NEM2 patients, each with unique mutations, aiming to understand their impact on mRNA, protein, and functional levels. Results show that truncation mutations affectNEBmRNA stability and lead to nonsense-mediated decay of the mutated transcript. Moreover, a high incidence of cryptic splice site activation was found in patients with splicing mutations which is expected to disrupt the actin-binding sites of nebulin. Determination of protein levels revealed patients with relatively normal nebulin levels and others with markedly reduced nebulin. We observed a positive relation between the reduction in nebulin and a reduction in TFL, and a positive relation between the reduction in nebulin level and the reduction in tension (both maximal and submaximal tension). Interestingly, our study revealed a duplication mutation in nebulin that resulted in a larger nebulin protein and longer TFL. Additionally, we investigated the effect of Omecamtiv mecarbil (OM), a small-molecule activator of cardiac myosin, on force production of type I muscle fibers of NEM2 patients. OM treatment substantially increased submaximal tension across all NEM2 patients ranging from 87-318%, with the largest effects in patients with the lowest level of nebulin. In summary, this study indicates that post-transcriptional or post-translational mechanisms regulate nebulin expression. Moreover, we propose that the pathomechanism of NEM2 involves not only shortened but also elongated thin filaments, along with the disruption of actin-binding sites resulting from splicing mutations. Significantly, our findings highlight the potential of OM treatment to improve skeletal muscle function in NEM2 patients, especially those with large reductions in nebulin levels.

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Loss of MuRF1 in Duroc pigs promotes skeletal muscle hypertrophy

et al. 2023

Transgenic Res

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BackgroundMuscle mass development depends on increased protein synthesis and reduced degradation of muscle proteins. Muscle ring-nger protein-1 (MuRF1) plays a key role in controlling muscle atrophy. Its E3 ubiquitin ligase activity recognizes and degrades skeletal muscle proteins through the ubiquitinproteasome system. The loss of Murf1 (the gene encoding MuRF1) in mice leads to the accumulation of skeletal muscle proteins and alleviation of muscle atrophy. However, the function of Murf1 in agricultural animals remains unclear. In this study, we bred F1 generation Murf1 +/− and F2 generation Murf1 −/− Duroc pigs from F0 Murf1 −/− pigs to investigate the effect of Murf1 knockout on skeletal muscle development. ResultsThe Murf1 +/− pigs retained normal muscle growth and reproduction levels, and their lean meat percentage increased by 6% compared to that of the wild-type (WT) pigs. Furthermore, the meat color, pH, water-holding capacity, and tenderness of the Murf1 +/− pigs were similar to those of the WT pigs. The drip loss rate and intramuscular fat decreased slightly in the Murf1 +/− pigs. However, the cross-sectional area of the myo bers in the longissimus dorsi increased in adult Murf1 +/− pigs. The skeletal muscle proteins MYBPC3 and actin, targeted by MuRF1, accumulated in the Murf1 +/− and Murf1 −/− pigs. ConclusionsOur ndings show that inhibiting muscle protein degradation in MuRF1-de cient Duroc pigs increases the size of their myo bers and percentage of lean meat without in uencing their growth or pork quality. Our study demonstrates that Murf1 is a target gene for promoting skeletal muscle hypertrophy in pig breeding.

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Removal of MuRF1 Increases Muscle Mass in Nemaline Myopathy Models, but Does Not Provide Functional Benefits

Cited by 3 publications

References 63 publications

Pharmacological Inhibition of Myostatin in a Mouse Model of Typical Nemaline Myopathy Increases Muscle Size and Force

Pharmacological Inhibition of Myostatin in a Mouse Model of Typical Nemaline Myopathy Increases Muscle Size and Force

Characterization ofNEBmutations in patients reveals novel nemaline myopathy disease mechanisms and omecamtiv mecarbil force effects

Loss of MuRF1 in Duroc pigs promotes skeletal muscle hypertrophy

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