Browsing by Subject "Muscle Strength"

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    Consistent improvement with eculizumab across muscle groups in myasthenia gravis.
    (Annals of clinical and translational neurology, 2020-08) Mantegazza, Renato; O'Brien, Fanny L; Yountz, Marcus; Howard, James F; REGAIN study group

    Objective

    To assess whether eculizumab, a terminal complement inhibitor, improves patient- and physician-reported outcomes (evaluated using the myasthenia gravis activities of daily living profile and the quantitative myasthenia gravis scale, respectively) in patients with refractory anti-acetylcholine receptor antibody-positive generalized myasthenia gravis across four domains, representing ocular, bulbar, respiratory, and limb/gross motor muscle groups.

    Methods

    Patients with refractory anti-acetylcholine receptor antibody-positive generalized myasthenia gravis were randomized 1:1 to receive either placebo or eculizumab during the REGAIN study (NCT01997229). Patients who completed REGAIN were eligible to continue into the open-label extension trial (NCT02301624) for up to 4 years. The four domain scores of each of the myasthenia gravis activities of daily living profile and the quantitative myasthenia gravis scale recorded throughout REGAIN and through 130 weeks of the open-label extension were analyzed.

    Results

    Of the 125 patients who participated in REGAIN, 117 enrolled in the open-label extension; 61 had received placebo and 56 had received eculizumab during REGAIN. Patients experienced rapid improvements in total scores and all four domain scores of both the myasthenia gravis activities of daily living profile and the quantitative myasthenia gravis scale with eculizumab treatment. These improvements were sustained through 130 weeks of the open-label extension.

    Interpretation

    Eculizumab treatment elicits rapid and sustained improvements in muscle strength across ocular, bulbar, respiratory, and limb/gross motor muscle groups and in associated daily activities in patients with refractory anti-acetylcholine receptor antibody-positive generalized myasthenia gravis.
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    Correlation between quantitative whole-body muscle magnetic resonance imaging and clinical muscle weakness in Pompe disease.
    (Muscle & nerve, 2015-05) Horvath, Jeffrey J; Austin, Stephanie L; Case, Laura E; Greene, Karla B; Jones, Harrison N; Soher, Brian J; Kishnani, Priya S; Bashir, Mustafa R

    Introduction

    Previous examination of whole-body muscle involvement in Pompe disease has been limited to physical examination and/or qualitative magnetic resonance imaging (MRI). In this study we assess the feasibility of quantitative proton-density fat-fraction (PDFF) whole-body MRI in late-onset Pompe disease (LOPD) and compare the results with manual muscle testing.

    Methods

    Seven LOPD patients and 11 disease-free controls underwent whole-body PDFF MRI. Quantitative MR muscle group assessments were compared with physical testing of muscle groups.

    Results

    The 95% upper limits of confidence intervals for muscle groups were 4.9-12.6% in controls and 6.8-76.4% in LOPD patients. LOPD patients showed severe and consistent tongue and axial muscle group involvement, with less marked involvement of peripheral musculature. MRI was more sensitive than physical examination for detection of abnormality in multiple muscle groups.

    Conclusion

    This integrated, quantitative approach to muscle assessment provides more detailed data than physical examination and may have clinical utility for monitoring disease progression and treatment response.
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    Increased inspiratory and expiratory muscle strength following respiratory muscle strength training (RMST) in two patients with late-onset Pompe disease.
    (Molecular genetics and metabolism, 2011-11) Jones, Harrison N; Moss, Tronda; Edwards, Laurie; Kishnani, Priya S
    Respiratory muscle strength training (RMST) is an exercise-based intervention which targets respiratory muscle weakness. We implemented RMST in two patients with late-onset Pompe disease (LOPD), both who had received long-term enzyme replacement therapy and had severe respiratory weakness. Over 16-32 weeks, inspiratory muscle strength increased by 73-74%. Expiratory muscle strength increased 31-48% over 12-22 weeks. These findings suggest that RMST may increase respiratory muscle strength, even in the setting of LOPD and severe baseline weakness.
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    Inspiratory Muscle Rehabilitation Training in Pediatrics: What Is the Evidence?
    (Canadian respiratory journal, 2022-01) Bhammar, Dharini M; Jones, Harrison N; Lang, Jason E
    Pulmonary rehabilitation is typically used for reducing respiratory symptoms and improving fitness and quality of life for patients with chronic lung disease. However, it is rarely prescribed and may be underused in pediatric conditions. Pulmonary rehabilitation can include inspiratory muscle training that improves the strength and endurance of the respiratory muscles. The purpose of this narrative review is to summarize the current literature related to inspiratory muscle rehabilitation training (IMRT) in healthy and diseased pediatric populations. This review highlights the different methods of IMRT and their effects on respiratory musculature in children. Available literature demonstrates that IMRT can improve respiratory muscle strength and endurance, perceived dyspnea and exertion, maximum voluntary ventilation, and exercise performance in the pediatric population. These mechanistic changes help explain improvements in symptomology and clinical outcomes with IMRT and highlight our evolving understanding of the role of IMRT in pediatric patients. There remains considerable heterogeneity in the literature related to the type of training utilized, training protocols, duration of the training, use of control versus placebo, and reported outcome measures. There is a need to test and refine different IMRT protocols, conduct larger randomized controlled trials, and include patient-centered clinical outcomes to help improve the evidence base and support the use of IMRT in patient care.
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    Long-term safety and efficacy of eculizumab in generalized myasthenia gravis.
    (Muscle & nerve, 2019-07) Muppidi, Srikanth; Utsugisawa, Kimiaki; Benatar, Michael; Murai, Hiroyuki; Barohn, Richard J; Illa, Isabel; Jacob, Saiju; Vissing, John; Burns, Ted M; Kissel, John T; Nowak, Richard J; Andersen, Henning; Casasnovas, Carlos; de Bleecker, Jan L; Vu, Tuan H; Mantegazza, Renato; O'Brien, Fanny L; Wang, Jing Jing; Fujita, Kenji P; Howard, James F; Regain Study Group

    Introduction

    Eculizumab is effective and well tolerated in patients with antiacetylcholine receptor antibody-positive refractory generalized myasthenia gravis (gMG; REGAIN; NCT01997229). We report an interim analysis of an open-label extension of REGAIN, evaluating eculizumab's long-term safety and efficacy.

    Methods

    Eculizumab (1,200 mg every 2 weeks for 22.7 months [median]) was administered to 117 patients.

    Results

    The safety profile of eculizumab was consistent with REGAIN; no cases of meningococcal infection were reported during the interim analysis period. Myasthenia gravis exacerbation rate was reduced by 75% from the year before REGAIN (P < 0.0001). Improvements with eculizumab in activities of daily living, muscle strength, functional ability, and quality of life in REGAIN were maintained through 3 years; 56% of patients achieved minimal manifestations or pharmacological remission. Patients who had received placebo during REGAIN experienced rapid and sustained improvements during open-label eculizumab (P < 0.0001).

    Discussion

    These findings provide evidence for the long-term safety and sustained efficacy of eculizumab for refractory gMG. Muscle Nerve 2019.
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    Quantitative assessment of lingual strength in late-onset Pompe disease.
    (Muscle & nerve, 2015-05) Jones, Harrison N; Crisp, Kelly D; Asrani, Priyanka; Sloane, Richard; Kishnani, Priya S

    Introduction

    Skeletal muscle is common in late-onset Pompe disease (LOPD). Recent data implicate common bulbar muscle involvement (i.e., the tongue).

    Methods

    We used quantitative assessment of lingual strength to retrospectively determine the frequency and severity of lingual weakness in LOPD. We additionally examined associations between lingual strength and the presence or absence of dysarthria, and dysarthria severity.

    Results

    Quantitative assessment revealed lingual weakness to be present in 80% of the sample. In the 24 affected patients, severity was mild in 29%, moderate in 29%, and severe in 42%. Patients with clinical dysarthria had greater lingual weakness than those without. As dysarthria severity increased, lingual strength decreased by an average of 6.82 kPa.

    Conclusions

    These quantitative data provide additional evidence for presence of bulbar muscle disease in patients with LOPD. Further study is necessary to determine functional effects, temporal progression, and effects of treatment.
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    Respiratory muscle training (RMT) in late-onset Pompe disease (LOPD): Effects of training and detraining.
    (Molecular genetics and metabolism, 2016-02) Jones, Harrison N; Crisp, Kelly D; Robey, Randall R; Case, Laura E; Kravitz, Richard M; Kishnani, Priya S

    Background

    Determine the effects of a 12-week respiratory muscle training (RMT) program in late-onset Pompe disease (LOPD).

    Methods

    We investigated the effects of 12-weeks of RMT followed by 3-months detraining using a single-subject A-B-A experimental design replicated across 8 adults with LOPD. To assess maximal volitional respiratory strength, our primary outcomes were maximum inspiratory pressure (MIP) and maximum expiratory pressure (MEP). Effect sizes for changes in MIP and MEP were determined using Cohen's d statistic. Exploratory outcomes targeted motor function, and peak cough flow (PCF) was measured in the last 5 subjects.

    Results

    From pretest to posttest, all 8 subjects exhibited increases in MIP, and 7 of 8 showed increases in MEP. Effect size data reveal the magnitude of increases in MIP to be large in 4 (d≥1.0) and very large in 4 (d≥2.0), and effect sizes for increases in MEP were large in 1 (d≥1.0) and very large in 6 (d≥2.0). Across participants, pretest to posttest MIP and MEP increased by a mean of 19.6% (sd=9.9) and 16.1% (sd=17.3), respectively. Respiratory strength increases, particularly for the inspiratory muscles, were generally durable to 3-months detraining.

    Conclusions

    These data suggest our 12-week RMT program results in large to very large increases in inspiratory and expiratory muscle strength in adults with LOPD. Additionally, increases in respiratory strength appeared to be relatively durable following 3-months detraining. Although additional research is needed, RMT appears to offer promise as an adjunctive treatment for respiratory weakness in LOPD.
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    Sarcopenia: no consensus, no diagnostic criteria, and no approved indication-How did we get here?
    (GeroScience, 2024-02) Evans, William J; Guralnik, Jack; Cawthon, Peggy; Appleby, James; Landi, Francesco; Clarke, Lindsay; Vellas, Bruno; Ferrucci, Luigi; Roubenoff, Ronenn
    In addition to the role of skeletal muscle in movement and locomotion, muscle plays a critical role in a broad array of metabolic processes that can contribute to improved health or risk of disease. The age-associated loss of muscle has been termed sarcopenia. The muscle is the primary site of insulin-stimulated glucose disposal and the largest component of basal metabolic rate, directly and indirectly affects bone density, produces myokines with pleiotropic effect on muscle and other tissues including the brain, and stores essential amino acids essential for the maintenance of protein synthesis during periods of reduced food intake and stress. As such, not surprisingly deterioration of skeletal muscle health, typically operationalized as decline of muscle mass and muscle strength is both a powerful risk factor and main consequence of chronic diseases, disability, and loss of independence, and it is one of the strongest risk factors for mortality. However, skeletal muscle remains one of the most plastic of all tissues, with rapid changes in rates of protein synthesis and degradation in response to physical activity and inactivity, inflammation, and nutritional and hormonal status. This has made the development of pharmacological therapies to increase muscle mass (or prevent loss), an important goal for decades. However, while remarkable advances in the understanding of molecular and cellular regulation of muscle protein metabolism have occurred recently, there are no approved drugs for the treatment of sarcopenia, the loss of skeletal muscle affecting millions of older people. The goal of this paper is to describe the possible reasons for the lack of new and effective pharmacotherapies to treat one of the most important risk factors for age-associated disease and loss of independence.
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    Training, detraining, and retraining: Two 12-week respiratory muscle training regimens in a child with infantile-onset Pompe disease.
    (Journal of pediatric rehabilitation medicine, 2020-01) Crisp, Kelly D; Case, Laura E; Kravitz, Richard M; Kishnani, Priya S; Jones, Harrison N

    Background

    Respiratory muscle weakness is a primary cause of morbidity and mortality in patients with Pompe disease. We previously described the effects of our 12-week respiratory muscle training (RMT) regimen in 8 adults with late-onset Pompe disease [1] and 2 children with infantile-onset Pompe disease [2].

    Case report

    Here we describe repeat enrollment by one of the pediatric participants who completed a second 12-week RMT regimen after 7 months of detraining. We investigated the effects of two 12-week RMT regimens (RMT #1, RMT #2) using a single-participant A-B-A experimental design. Primary outcome measures were maximum inspiratory pressure (MIP) and maximum expiratory pressure (MEP). Effect sizes for changes in MIP and MEP were determined using Cohen's d statistic. Exploratory outcomes targeted motor function.

    Relevance

    From pretest to posttest, RMT #2 was associated with a 25% increase in MIP and a 22% increase in MEP, corresponding with very large effect sizes (d= 2.92 and d= 2.65, respectively). Following two 12-week RMT regimens over 16 months, MIP increased by 69% and MEP increased by 97%, corresponding with very large effect sizes (d= 3.57 and d= 5.10, respectively). MIP and MEP were largely stable over 7 months of detraining between regimens. Magnitude of change was greater for RMT #1 relative to RMT #2.
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    β-arrestin 1 regulates β2-adrenergic receptor-mediated skeletal muscle hypertrophy and contractility.
    (Skeletal muscle, 2018-12-27) Kim, Jihee; Grotegut, Chad A; Wisler, James W; Li, Tianyu; Mao, Lan; Chen, Minyong; Chen, Wei; Rosenberg, Paul B; Rockman, Howard A; Lefkowitz, Robert J
    BACKGROUND:β2-adrenergic receptors (β2ARs) are the target of catecholamines and play fundamental roles in cardiovascular, pulmonary, and skeletal muscle physiology. An important action of β2AR stimulation on skeletal muscle is anabolic growth, which has led to the use of agonists such as clenbuterol by athletes to enhance muscle performance. While previous work has demonstrated that β2ARs can engage distinct signaling and functional cascades mediated by either G proteins or the multifunctional adaptor protein, β-arrestin, the precise role of β-arrestin in skeletal muscle physiology is not known. Here, we tested the hypothesis that agonist activation of the β2AR by clenbuterol would engage β-arrestin as a key transducer of anabolic skeletal muscle growth. METHODS:The contractile force of isolated extensor digitorum longus muscle (EDL) and calcium signaling in isolated flexor digitorum brevis (FDB) fibers were examined from the wild-type (WT) and β-arrestin 1 knockout mice (βarr1KO) followed by chronic administration of clenbuterol (1 mg/kg/d). Hypertrophic responses including fiber composition and fiber size were examined by immunohistochemical imaging. We performed a targeted phosphoproteomic analysis on clenbuterol stimulated primary cultured myoblasts from WT and βarr1KO mice. Statistical significance was determined by using a two-way analysis with Sidak's or Tukey's multiple comparison test and the Student's t test. RESULTS:Chronic administration of clenbuterol to WT mice enhanced the contractile force of EDL muscle and calcium signaling in isolated FDB fibers. In contrast, when administered to βarr1KO mice, the effect of clenbuterol on contractile force and calcium influx was blunted. While clenbuterol-induced hypertrophic responses were observed in WT mice, this response was abrogated in mice lacking β-arrestin 1. In primary cultured myoblasts, clenbuterol-stimulated phosphorylation of multiple pro-hypertrophy proteins required the presence of β-arrestin 1. CONCLUSIONS:We have identified a previously unappreciated role for β-arrestin 1 in mediating β2AR-stimulated skeletal muscle growth and strength. We propose these findings could have important implications in the design of future pharmacologic agents aimed at reversing pathological conditions associated with skeletal muscle wasting.