No abstract

Two highly prevalent and growing global diseases impacted by skeletal muscle atrophy are chronic heart failure (HF) and type 2 diabetes mellitus (DM). The presence of either condition increases the likelihood of developing the other, with recent studies revealing a large and relatively poorly characterized clinical population of patients with coexistent HF and DM (HFDM). HFDM results in worse symptoms and poorer clinical outcomes compared with DM or HF alone, and cardiovascular‐focused disease‐modifying agents have proven less effective in HFDM indicating a key role of the periphery. This review combines current clinical knowledge and basic biological mechanisms to address the critical emergence of skeletal muscle atrophy in patients with HFDM as a key driver of symptoms. We discuss how the degree of skeletal muscle wasting in patients with HFDM is likely underpinned by a variety of mechanisms that include mitochondrial dysfunction, insulin resistance, inflammation, and lipotoxicity. Given many atrophic triggers (e.g. ubiquitin proteasome/autophagy/calpain activity and supressed IGF1‐Akt‐mTORC1 signalling) are linked to increased production of reactive oxygen species, we speculate that a higher pro‐oxidative state in HFDM could be a unifying mechanism that promotes accelerated fibre atrophy. Overall, our proposal is that patients with HFDM represent a unique clinical population, prompting a review of treatment strategies including further focus on elucidating potential mechanisms and therapeutic targets of muscle atrophy in these distinct patients.

No abstract

Increasing evidence links changes in epigenetic systems, such as DNA methylation, histone modification and non-coding RNA expression, to the occurrence of cardiovascular disease (CVD). These epigenetic modifications can change genetic function under influence of exogenous stimuli, and can be transferred to next generations, providing a potential mechanism for inheritance of behavioral intervention effects. The benefits of exercise and nutritional interventions in the primary and secondary prevention of CVD are well established, but the mechanisms are not completely understood. In this review, we describe the acute and chronic epigenetic effects of physical activity and dietary changes. We propose exercise and nutrition as potential triggers of epigenetic signals, promoting the reshaping of transcriptional programs with effects on CVD phenotypes. Finally, we highlight recent developments in epigenetic therapeutics with implications for primary and secondary CVD prevention.

Skeletal muscle atrophy is a common clinical feature of many acute and chronic conditions. Circular RNAs (circRNAs) are covalently closed RNA transcripts that are involved in various physiological and pathological processes, but their role in muscle atrophy remains unknown. Global circRNA expression profiling indicated that circRNAs are involved in the pathophysiological processes of muscle atrophy. circTmeff1 is identified as a potential circRNA candidate that influences muscle atrophy. It is further identified that circTmeff1 is highly expressed in multiple types of muscle atrophy in vivo and in vitro. Moreover, the overexpression of circTmeff1 triggers muscle atrophy in vitro and in vivo, while the knockdown of circTmeff1 expression rescues muscle atrophy in vitro and in vivo. In particular, the knockdown of circTmeff1 expression partially rescues muscle mass in mice during established atrophic settings. Mechanistically, circTmeff1 directly interacts with TAR DNA-binding protein 43 (TDP-43) and promotes aggregation of TDP-43 in mitochondria, which triggers the release of mitochondrial DNA (mtDNA) into cytosol and activation of the cyclic GMP-AMP synthase (cGAS)/ stimulator of interferon genes (STING) pathway. Unexpectedly, TMEFF1-339aa is identified as a novel protein encoded by circTmeff1 that mediates its pro-atrophic effects. Collectively, the inhibition of circTmeff1 represents a novel therapeutic approach for multiple types of skeletal muscle atrophy.