Non-technical summary Wasting and severely impaired function of skeletal muscle is frequently observed in critically ill intensive care unit (ICU) patients, with negative consequences for recovery and quality of life. An experimental rat ICU model has been used to study the mechanisms underlying this unique wasting condition in neuromuscularly blocked and mechanically ventilated animals at durations varying between 6 h and 2 weeks. The complete 'mechanical silencing' of skeletal muscle (removal of both weight bearing and activation) resulted in a specific myopathy frequently observed in ICU patients and characterized by a preferential loss of the motor protein myosin. A highly complex and coordinated protein synthesis and degradation system was observed in the time-resolved analyses. It is suggested the 'mechanical silencing' of skeletal muscle is a dominating factor triggering the specific myopathy associated with the ICU intervention, and strongly supporting the importance of interventions counteracting the complete unloading in ICU patients. AbstractThe muscle wasting and impaired muscle function in critically ill intensive care unit (ICU) patients delay recovery from the primary disease, and have debilitating consequences that can persist for years after hospital discharge. It is likely that, in addition to pernicious effects of the primary disease, the basic life support procedures of long-term ICU treatment contribute directly to the progressive impairment of muscle function. This study aims at improving our understanding of the mechanisms underlying muscle wasting in ICU patients by using a unique experimental rat ICU model where animals are mechanically ventilated, sedated and pharmacologically paralysed for duration varying between 6 h and 14 days. Results show that the ICU intervention induces a phenotype resembling the severe muscle wasting and paralysis associated with the acute quadriplegic myopathy (AQM) observed in ICU patients, i.e. a preferential loss of myosin, transcriptional down-regulation of myosin synthesis, muscle atrophy and a dramatic decrease in muscle fibre force generation capacity. Detailed analyses of protein degradation pathways show that the ubiquitin proteasome pathway is highly involved in this process. A sequential change in localisation of muscle-specific RING finger proteins 1/2 (MuRF1/2) observed during the experimental period is suggested to play an instrumental role in both transcriptional regulation and protein degradation. We propose that, for those critically ill patients who develop AQM, complete mechanical silencing, due to pharmacological paralysis or sedation, is a critical factor underlying the preferential loss of the molecular motor protein myosin that leads to impaired muscle function or persisting paralysis.

Clinical, genetic and pathological studies all demonstrate that mutations in glucocerebrosidase (GBA), which encodes the lysosomal enzyme deficient in Gaucher disease (GD), are an important and common risk factor for Parkinson disease (PD) and related disorders. Some patients with GD and Gaucher carriers develop parkinsonism. Furthermore, subjects with PD have a greatly increased frequency of GBA mutations. GBA mutation carriers exhibit diverse parkinsonian phenotypes, and have glucocerebrosidase-positive Lewy bodies. Although the mechanism for this association is unknown, we present several theories, including enhanced protein aggregation, prion transmission, lipid accumulation, and impaired autophagy, mitophagy or trafficking. Each has inherent limitations, and an unknown “second hit” might be essential. Elucidating the basis for this link will have important consequences and should provide new insights into lysosomal pathways and potential treatment strategies.

Key points• Early physical mobilization of mechanically ventilated intensive care unit (ICU) patients can reduce the length of stay in the ICU and hospital and improve muscle strength and functional outcomes.• A unique experimental rat ICU model has been used to study the effects and underlying mechanisms of unilateral passive mechanical loading on skeletal muscle size and function at durations varying between 6 h and 2 weeks.• Passive mechanical loading attenuated the loss of muscle mass and force-generation capacity associated with the ICU intervention.• The maintained muscle mass and function by passive loading is probably due to lower oxidative stress and a reduced loss of the molecular motor protein myosin.• The beneficial effects of passive mechanical loading on muscle size and function strongly support the importance of early and intense physical therapy in immobilized ICU patients.Abstract The response to mechanical stimuli, i.e. tensegrity, plays an important role in regulating cell physiological and pathophysiological function, and the mechanical silencing observed in intensive care unit (ICU) patients leads to a severe and specific muscle wasting condition. This study aims to unravel the underlying mechanisms and the effects of passive mechanical loading on skeletal muscle mass and function at the gene, protein and cellular levels. A unique experimental rat ICU model has been used allowing long-term (weeks) time-resolved analyses of the effects of standardized unilateral passive mechanical loading on skeletal muscle size and function and underlying mechanisms. Results show that passive mechanical loading alleviated the muscle wasting and the loss of force-generation associated with the ICU intervention, resulting in a doubling of the functional capacity of the loaded versus the unloaded muscles after a 2-week ICU intervention. We demonstrate that the improved maintenance of muscle mass and function is probably a consequence of a reduced oxidative stress revealed by lower levels of carbonylated proteins, and a reduced loss of the molecular motor protein myosin. A complex temporal gene expression pattern, delineated by microarray analysis, was observed with loading-induced changes in transcript levels of sarcomeric proteins, muscle developmental processes, stress response, extracellular matrix/cell adhesion proteins and metabolism. Thus, the results from this study show that passive mechanical loading alleviates the severe negative consequences on muscle size * G. Renaud and M. Llano-Diez contributed equally to this paper

Mucolipidosis type IV (MLIV) is a neurodevelopmental as well as neurodegenerative disorder with severe psychomotor developmental delay, progressive visual impairment, and achlorydria. It is characterized by the presence of lysosomal inclusions in many cell types in patients. MLIV is an autosomal recessive disease caused by mutations in MCOLN1, which encodes for mucolipin-1, a member of the transient receptor potential (TRP) cation channel family. Although approximately 70-80% of patients identified are Ashkenazi Jewish, MLIV is a pan-ethnic disorder. Importantly, while MLIV is thought to be a rare disease, its frequency may be greater than currently appreciated, for its common presentation as a cerebral palsy-like encephalopathy can lead to misdiagnosis. Moreover, patients with milder variants are often not recognized as having MLIV. This review provides an update on the ethnic distribution, clinical manifestations, laboratory findings, methods of diagnosis, molecular genetics, differential diagnosis, and treatment of patients with MLIV. An enhanced awareness of the manifestations of this disorder may help to elucidate the true frequency and range of symptoms associated with MLIV, providing insight into the pathogenesis of this multi-system disease.