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.
Highlights
Skeletal muscle is one of the largest organs in the human body, accounting for approximately 40% of total body mass and acting as a major site for both protein storage and glucose disposal.[1]
This highlights the importance of implementing exercise training in patients with HF and DM (HFDM) as a treatment for muscle atrophy.[2] skeletal muscle levels of these key pro‐inflammatory cytokines have been reported to be elevated in patients with HF67,68,92 and diabetes mellitus (DM),[68,93] which strongly correlate with mortality.[92]
The prevalence of HFDM is increasing globally, and these patients have worse symptoms and poorer survival compared to patients with heart failure (HF) or DM alone, while traditional pharmacological treatments show limited benefits
Summary
Skeletal muscle is one of the largest organs in the human body, accounting for approximately 40% of total body mass and acting as a major site for both protein storage and glucose disposal.[1]. Impaired insulin sensitivity can lead to hyperglycaemia, and while direct data from humans are missing, animal models of DM have shown a causal link to fibre atrophy via the WWP1/KLF15 pathway[86] as well as contractile dysfunction,[86,87] ROS,[88] and endothelial dysfunction.[89] Further evidence indicates that a reduction in muscle contractions per se can drive the development of insulin resistance and in combination with a systemic inflammation, can impair insulin insensitivity to further exacerbate muscle wasting by reducing protein synthesis and elevating protein degradation.[52] This highlights the importance of implementing exercise training in patients with HFDM as a treatment for muscle atrophy.[2] skeletal muscle levels of these key pro‐inflammatory cytokines have been reported to be elevated in patients with HF67,68,92 and DM,[68,93] which strongly correlate with mortality.[92] In relation to HFDM, our knowledge is limited, but recent network analyses of blood samples in two separate studies have identified inflammation as being an up‐regulated pathway in patients with HFDM compared with those with HF30,31 but muscle atrophy was not measured in this study Overall, it seems that inflammation is higher in patients with HFDM vs HF or DM, which could act as a major upstream mechanism accelerating fibre atrophy. There are not enough data to accept or refute these notions, with more extensive data and interventions required to answer this question, which is further limited by the lack of adequate pre‐clinical experimental models of HFDM that closely reflect the patient and skeletal muscle phenotype
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