Autophagy is a catabolic process that ensures homeostatic cell clearance and is deregulated in a growing number of myopathological conditions. Although FoxO3 was shown to promote the expression of autophagy-related genes in skeletal muscle, the mechanisms triggering autophagy are unclear. We show that TSC1-deficient mice (TSCmKO), characterized by sustained activation of mTORC1, develop a late-onset myopathy related to impaired autophagy. In young TSCmKO mice, constitutive and starvation-induced autophagy is blocked at the induction steps via mTORC1-mediated inhibition of Ulk1, despite FoxO3 activation. Rapamycin is sufficient to restore autophagy in TSCmKO mice and improves the muscle phenotype of old mutant mice. Inversely, abrogation of mTORC1 signaling by depletion of raptor induces autophagy regardless of FoxO inhibition. Thus, mTORC1 is the dominant regulator of autophagy induction in skeletal muscle and ensures a tight coordination of metabolic pathways. These findings may open interesting avenues for therapeutic strategies directed toward autophagy-related muscle diseases.

With human median lifespan extending into the 80s in many developed countries, the societal burden of age-related muscle loss (sarcopenia) is increasing. mTORC1 promotes skeletal muscle hypertrophy, but also drives organismal aging. Here, we address the question of whether mTORC1 activation or suppression is beneficial for skeletal muscle aging. We demonstrate that chronic mTORC1 inhibition with rapamycin is overwhelmingly, but not entirely, positive for aging mouse skeletal muscle, while genetic, muscle fiber-specific activation of mTORC1 is sufficient to induce molecular signatures of sarcopenia. Through integration of comprehensive physiological and extensive gene expression profiling in young and old mice, and following genetic activation or pharmacological inhibition of mTORC1, we establish the phenotypically-backed, mTORC1-focused, multi-muscle gene expression atlas, SarcoAtlas (https://sarcoatlas.scicore.unibas.ch/), as a user-friendly gene discovery tool. We uncover inter-muscle divergence in the primary drivers of sarcopenia and identify the neuromuscular junction as a focal point of mTORC1-driven muscle aging.

Based on the described clinical features, normal nerve conduction studies, characteristic somatosensory evoked potential (SSEP) abnormality, enlarged nerve roots, elevated CSF protein, and inflammatory hypertrophic changes of sensory nerve rootlet tissue, we suggest the term chronic immune sensory polyradiculopathy (CISP) for this syndrome. This condition preferentially affects large myelinated fibers of the posterior roots, may respond favorably to treatment, and may be a restricted form of chronic inflammatory demyelinating polyradiculoneuropathy.

Altered autophagy contributes to the pathogenesis of Alzheimer’s disease and other tauopathies, for which curative treatment options are still lacking. We have recently shown that trehalose reduces tau pathology in a tauopathy mouse model by stimulation of autophagy. Here, we studied the effect of the autophagy inducing drug rapamycin on the progression of tau pathology in P301S mutant tau transgenic mice. Rapamycin treatment resulted in a significant reduction in cortical tau tangles, less tau hyperphosphorylation, and lowered levels of insoluble tau in the forebrain. The favourable effect of rapamycin on tau pathology was paralleled by a qualitative reduction in astrogliosis. These effects were visible with early preventive or late treatment. We further noted an accumulation of the autophagy associated proteins p62 and LC3 in aged tangle bearing P301S mice that was lowered upon rapamycin treatment. Thus, rapamycin treatment defers the progression of tau pathology in a tauopathy animal model and autophagy stimulation may constitute a therapeutic approach for patients suffering from tauopathies.

An early sign of human myoblast commitment to fusion is the expression of a non-inactivating delayed rectifier K + current, I K(NI) , and an associated membrane potential hyperpolarization. We have isolated the full-length coding region of a human ether-a-go-go K + channel (h-eag) from myoblasts undergoing differentiation. The h-eag gene was localized to chromosome 1q32^41, and is expressed as a V9 kb transcript in myogenic cells and in adult brain tissue. Forced expression of h-eag in undifferentiated myoblasts generates a current with remarkable similarity to I K(NI) indicating that h-eag constitutes the channel responsible for this current in vivo.z 1998 Federation of European Biochemical Societies.

Dysferlin is a type II transmembrane protein implicated in Ca(2+)-dependent sarcolemmal membrane repair. Dysferlin has seven C2 domains, which are lipid and protein binding modules. In this study, we sought to characterize the lipid binding specificity of dysferlin's seven C2 domains. Dysferlin's C2A domain was able to bind to phosphatidylserine (PS), phosphatidylinositol 4-phosphate [PtdIns(4)P], and phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P(2)] in a Ca(2+)-dependent fashion. The remainder of the C2 domains exhibited weaker and Ca(2+)-independent binding to PS and no significant binding to phosphoinositides.

Comparison of these results with those of studies comparing healthy glycolytic with oxidative muscle suggests that these differences may be attributable to greater type II fiber expression in COPD muscle, as mitochondria within this fiber type have respiratory function similar to that of mitochondria from type I fibers, and yet are intrinsically prone to greater release of H(2)O(2) and more resistant to PTP opening. These results thus argue against the presence of pathological mitochondrial alterations in this category of patients with COPD.

Ultrasound is useful for non-invasive visualization of focal nerve pathologies probably resulting from demyelination, remyelination, edema or inflammation. In patients with progressive muscle weakness, differentiation between multifocal motor neuropathy (MMN) and amyotrophic lateral sclerosis (ALS) is essential regarding therapy and prognosis. Therefore, the objective of this study was to investigate whether nerve ultrasound can differentiate between ALS and MMN. Systematic ultrasound measurements of peripheral nerves and the 6th cervical nerve root (C6) were performed in 17 patients with ALS, in 8 patients with MMN and in 28 healthy controls. Nerve conduction studies of corresponding nerves were undertaken in MMN and ALS patients. Electromyography was performed in ALS patients according to revised El-Escorial criteria. ANOVA and unpaired t test with Bonferroni correction revealed significant differences in cross-sectional areas (CSA) of different nerves and C6 diameter between the groups. Nerve enlargement was found significantly more frequently in MMN than in other groups (p < 0.001). Receiver operating characteristics analysis revealed detection of enlarged nerves/roots in at least four measurement points to serve as a good marker to differentiate MMN from ALS with a sensitivity of 87.5% and a specificity of 94.1%. Ultrasonic focal nerve enlargement in MMN was often not colocalized with areas of conduction blocks found in nerve conduction studies. Systematic ultrasound measurements in different nerves and nerve roots are valuable for detecting focal nerve enlargement in MMN, generally not found in ALS and thus could serve as a diagnostic marker to differentiate between both entities in addition to electrodiagnostic studies.