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Illness-associated muscle weakness in dystroglycanopathies.

ABSTRACT: OBJECTIVE:To describe the phenomenon of acute illness-associated weakness (AIAW) in patients with dystroglycanopathy (DG), determine the frequency of this phenomenon in DGs, and compare it to the frequency in Duchenne-Becker muscular dystrophy (DBMD). METHODS:Patients enrolled in a DG natural history study provided medical history, including major illnesses or hospitalizations, at enrollment and annually. We noted a recurring syndrome of profound transient weakness in the setting of febrile illness. To determine the frequency of this phenomenon in the DG cohort and compare it to a cohort with another membrane-related muscular dystrophy, DBMD, we surveyed patients (e-survey tool), collecting demographics and information about episodes of sudden progression of weakness and events surrounding the episodes. RESULTS:Surveys were completed by 52 (56.6%) patients with DG and 51 (27.3%) patients with DBMD. AIAW was reported in 12 (23%) patients with DG and 2 (4%) patients with DBMD (odds ratio 7.35; 95% confidence interval 1.55, 34.77; p = 0.005). Altogether (history or survey), 21 patients with DG, with mutations in FKRP, FKTN, POMT1, POMT2, or POMGNT1, reported AIAW. These events typically occurred in children <7 years old, and the preceding illness usually included respiratory symptoms. In 10 (47.6%) patients with DG, AIAW preceded the diagnosis of muscular dystrophy. CONCLUSIONS:People with DG, across genotypes, can experience acute, transient weakness associated with a febrile illness, a phenomenon that rarely occurs in DBMD. The physiologic basis of this phenomenon is unknown. CLINICALTRIALSGOV IDENTIFIER:NCT00313677.

SUBMITTER: Carlson CR

PROVIDER: S-EPMC5719925 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Premorbid obesity, but not nutrition, prevents critical illness-induced muscle wasting and weakness.

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| S-EPMC5326828 | biostudies-literature

Altered cholesterol homeostasis in critical illness-induced muscle weakness: effect of exogenous 3-hydroxybutyrate.

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| S-EPMC8285799 | biostudies-literature

Transcriptomic analysis reveals abnormal repair and remodeling in survivors of critical illness with sustained muscle weakness

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2016-07-18 | GSE78929 | GEO

Transcriptomic analysis reveals abnormal repair and remodeling in survivors of critical illness with sustained muscle weakness

2016-07-18 | E-GEOD-78929 | biostudies-arrayexpress

Mitochondrial function in skeletal muscle of patients with protracted critical illness and ICU-acquired weakness.

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| S-EPMC4699339 | biostudies-literature

Transcriptomic analysis reveals abnormal muscle repair and remodeling in survivors of critical illness with sustained weakness.

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Excess TGF-? mediates muscle weakness associated with bone metastases in mice.

Project description:Cancer-associated muscle weakness is a poorly understood phenomenon, and there is no effective treatment. Here we find that seven different mouse models of human osteolytic bone metastases-representing breast, lung and prostate cancers, as well as multiple myeloma-exhibited impaired muscle function, implicating a role for the tumor-bone microenvironment in cancer-associated muscle weakness. We found that transforming growth factor (TGF)-?, released from the bone surface as a result of metastasis-induced bone destruction, upregulated NADPH oxidase 4 (Nox4), resulting in elevated oxidization of skeletal muscle proteins, including the ryanodine receptor and calcium (Ca(2+)) release channel (RyR1). The oxidized RyR1 channels leaked Ca(2+), resulting in lower intracellular signaling, which is required for proper muscle contraction. We found that inhibiting RyR1 leakage, TGF-? signaling, TGF-? release from bone or Nox4 activity improved muscle function in mice with MDA-MB-231 bone metastases. Humans with breast- or lung cancer-associated bone metastases also had oxidized skeletal muscle RyR1 that is not seen in normal muscle. Similarly, skeletal muscle weakness, increased Nox4 binding to RyR1 and oxidation of RyR1 were present in a mouse model of Camurati-Engelmann disease, a nonmalignant metabolic bone disorder associated with increased TGF-? activity. Thus, pathological TGF-? release from bone contributes to muscle weakness by decreasing Ca(2+)-induced muscle force production.

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| S-EPMC4863830 | biostudies-literature

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