Skeletal muscle atrophy in heart failure with diabetes: from molecular mechanisms to clinical evidence.

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.