Autophagy is stimulated by exercise in several tissues; yet the role of skeletal and cardiac muscle-specific autophagy on the benefits of exercise training remains incompletely understood. Here, we determined the metabolic impact of exercise training in obese mice with cardiac and skeletal muscle disruption of the Autophagy related 7 gene (Atg7h&mKO). Muscle autophagy deficiency did not affect glucose clearance and exercise capacity in lean adult mice. High-fat diet in sedentary mice led to endoplasmic reticulum stress and aberrant mitochondrial protein expression in autophagy-deficient skeletal and cardiac muscles. Endurance exercise training partially reversed these abnormalities in skeletal muscle, but aggravated those in the heart also causing cardiac fibrosis, foetal gene reprogramming, and impaired mitochondrial biogenesis. Interestingly, exercise-trained Atg7h&mKO mice were better protected against obesity and insulin resistance with increased circulating fibroblast growth factor 21 (FGF21), elevated Fgf21 mRNA and protein solely in the heart, and upregulation of FGF21-target genes involved in thermogenesis and fatty acid oxidation in brown fat. These results indicate that autophagy is essential for the protective effects of exercise in the heart. However, the atypical remodelling elicited by exercise in the autophagy deficient cardiac muscle enhances whole-body metabolism, at least partially, via a heart-brown fat cross-talk involving FGF21.

Basal protein turnover, which largely relies on the degradation of ubiquitinated substrates, is instrumental for maintenance of muscle mass and function. However, the regulation of ubiquitinated protein degradation in healthy, nonatrophying skeletal muscle is still evolving, and potential tissue-specific modulators remain unknown. Using an unbiased expression analysis of 34 putative autophagy genes across mouse tissues, we identified unc-51 like autophagy activating kinase (Ulk)2, a homolog of the yeast autophagy related protein 1, as particularly enriched in skeletal muscle. Subsequent experiments revealed accumulations of insoluble ubiquitinated protein aggregates associated with the adaptors sequestosome 1 (SQSTM1, also known as p62) and next to breast cancer type 1 susceptibility protein gene 1 protein (NBR1) in adult muscles with ULK2 deficiency. ULK2 deficiency also led to impaired muscle force and caused myofiber atrophy and degeneration. These features were not observed in muscles with deficiency of the ULK2 paralog, ULK1. Furthermore, short-term ULK2 deficiency did not impair autophagy initiation, autophagosome to lysosome fusion, or protease activities of the lysosome and proteasome. Altogether, our results indicate that skeletal muscle ULK2 has a unique role in basal selective protein degradation by stimulating the recognition and proteolytic sequestration of insoluble ubiquitinated protein aggregates associated with p62 and NBR1. These findings have potential implications for conditions of poor protein homeostasis in muscles as observed in several myopathies and aging.—Fuqua, J. D., Mere, C. P., Kronemberger, A., Blomme, J., Bae, D., Turner, K. D., Harris, M. P., Scudese, E., Edwards, M., Ebert, S. M., de Sousa, L. G. O., Bodine, S. C., Yang, L., Adams, C. M., Lira, V. A. ULK2 is essential for degradation of ubiquitinated protein aggregates and homeostasis in skeletal muscle.

What factors are associated with spontaneous clearance of hepatitis C infection among adults? EVIDENCE-BASED ANSWERTwo polymorphisms of the IL28B gene are associated with an increase in hepatitis C virus (HCV) clearance (SOR: C, meta-analysis of cohort and case-control studies). Multiple human leukocyte antigen alleles have been associated with an increase in spontaneous HCV resolution, of which DQB1*03, DRB1*04, and DRB1*11 show the strongest results (SOR: C, metaanalysis of peer-reviewed studies). Aside from genetic factors, male sex, asymptomatic infection, Black race, and absence of hepatitis B coinfection were found to negatively correlate with spontaneous clearance (SOR: C, meta-analysis of observational studies).