Bjarne Udd and colleagues show that mutations affecting the cytoplasmic functions of the co-chaperone DNAJB6 result in limb-girdle muscular dystrophy. Their studies suggest that the mutations reduce the protective anti-aggregation effects of DNAJB6, leading to protein accumulation and autophagic pathology. Limb-girdle muscular dystrophy type 1D (LGMD1D) was linked to chromosome 7q36 over a decade ago1, but its genetic cause has remained elusive. Here we studied nine LGMD-affected families from Finland, the United States and Italy and identified four dominant missense mutations leading to p.Phe93Leu or p.Phe89Ile changes in the ubiquitously expressed co-chaperone DNAJB6. Functional testing in vivo showed that the mutations have a dominant toxic effect mediated specifically by the cytoplasmic isoform of DNAJB6. In vitro studies demonstrated that the mutations increase the half-life of DNAJB6, extending this effect to the wild-type protein, and reduce its protective anti-aggregation effect. Further, we show that DNAJB6 interacts with members of the CASA complex, including the myofibrillar myopathy–causing protein BAG3. Our data identify the genetic cause of LGMD1D, suggest that its pathogenesis is mediated by defective chaperone function and highlight how mutations in a ubiquitously expressed gene can exert effects in a tissue-, isoform- and cellular compartment–specific manner.

Obesity and type 2 diabetes are growing health problems worldwide. The three principal diabetogenic factors are adiposity, insulin resistance in skeletal muscle, and decreased insulin production by pancreatic β cells. During recent years, macroautophagy (hereafter autophagy) — sequestration and lysosomal degradation of cellular components — has emerged as an important player in these processes, playing a protective role against development of insulin resistance and diabetes. Of particular importance is the removal of dysfunctional mitochondria via mitophagy, a form of macroautophagy selective for mitochondria. Both muscle insulin resistance and β-cell dysfunction largely depend on metabolic overload of mitochondria, which results in incomplete β-oxidation, oxidative stress, accumulation of toxic lipid intermediates, and mitochondrial damage. Mitophagy eliminates this vicious cycle of oxidative stress and mitochondrial damage, and thus counteracts pathogenic processes. Autophagy also mediates exercise-induced increases in muscle glucose uptake and protects β cells against ER stress in diabetogenic conditions. On the other hand, adipose tissue autophagy promotes adipocyte differentiation, possibly through its role in mitochondrial clearance. Being involved in many aspects, autophagy appears to be an attractive target for therapeutic interventions against obesity and diabetes. Here we explore the connections of autophagy with mitochondria in obesity and type 2 diabetes, and discuss its roles in diabetic complications. Understanding how autophagy protects against diabetes could help design new strategies against this growing epidemic.

The TTN gene with 363 coding exons encodes titin, a giant muscle protein spanning from the Z-disk to the M-band within the sarcomere. Mutations in the TTN gene have been associated with different genetic disorders, including hypertrophic and dilated cardiomyopathy and several skeletal muscle diseases. Before the introduction of next generation sequencing (NGS) methods, the molecular analysis of TTN has been laborious, expensive and not widely used, resulting in a limited number of mutations identified. Recent studies however, based on the use of NGS strategies, give evidence of an increasing number of rare and unique TTN variants. The interpretation of these rare variants of uncertain significance (VOUS) represents a challenge for clinicians and researchers. The main aim of this review is to describe the wide spectrum of muscle diseases caused by TTN mutations so far determined, summarizing the molecular findings as well as the clinical data, and to highlight the importance of joint efforts to respond to the challenges arising from the use of NGS. An international collaboration through a clinical and research consortium and the development of a single accessible database listing variants in the TTN gene, identified by high throughput approaches, may be the key to a better assessment of titinopathies and to systematic genotype– phenotype correlation studies.

Multisystem proteinopathy (MSP) involves disturbances of stress granule (SG) dynamics and autophagic protein degradation that underlie the pathogenesis of a spectrum of degenerative diseases that affect muscle, brain, and bone. Specifically, identical mutations in the autophagic adaptor SQSTM1 can cause varied penetrance of 4 distinct phenotypes: amyotrophic lateral sclerosis (ALS), frontotemporal dementia, Paget’s disease of the bone, and distal myopathy. It has been hypothesized that clinical pleiotropy relates to additional genetic determinants, but thus far, evidence has been lacking. Here, we provide evidence that a TIA1 (p.N357S) variant dictates a myodegenerative phenotype when inherited, along with a pathogenic SQSTM1 mutation. Experimentally, the TIA1-N357S variant significantly enhances liquid-liquid–phase separation in vitro and impairs SG dynamics in living cells. Depletion of SQSTM1 or the introduction of a mutant version of SQSTM1 similarly impairs SG dynamics. TIA1-N357S–persistent SGs have increased association with SQSTM1, accumulation of ubiquitin conjugates, and additional aggregated proteins. Synergistic expression of the TIA1-N357S variant and a SQSTM1-A390X mutation in myoblasts leads to impaired SG clearance and myotoxicity relative to control myoblasts. These findings demonstrate a pathogenic connection between SG homeostasis and ubiquitin-mediated autophagic degradation that drives the penetrance of an MSP phenotype.