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

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.

Physical Rehabilitation in Older Patients Hospitalized with Acute Heart Failure and Diabetes: Insights from REHAB-HF

“…Diabetes and heart failure synergistically contribute to severely decreased physical function through skeletal muscle atrophy, inflammation, and metabolic dysfunction. 21 Levels of cardiac dysfunction may correlate poorly with symptoms, 22,23 and exercise training, although associated with improved physical function, 6 has relatively little effect on cardiac function in heart failure. 24,25 The benefits of physical rehabilitation and exercise are thought to be primarily through peripheral mechanisms such as improved skeletal muscle, mitochondrial, and microvascular function.…”

“…Muscle strength among heart failure patients with diabetes is impaired compared with patients without diabetes, 28 potentially as a result of mitochondrial dysfunction, reactive oxygen species generation, insulin resistance, lipotoxicity, and inflammation. 21 Other complications of diabetes can lead to significant impairments in mobility and physical function. Patients with diabetes often have concurrent peripheral neuropathy, which can impair balance and proprioception, leading to reduced functional performance and stability.…”

Utility of a Score for Predicting Glomerular Filtration Rate Overestimation in Patients with Cardiovascular and Renal Diseases and Their Risk Factors

“…Thus, the serum cystatin C level might be elevated by an increase in the BMI, possibly through subclinical inflammation ( 10 , 19 - 21 ) but not a decline in the renal function, leading to discordance between eGFRcre and eGFRcys. In addition, muscle wasting is frequently observed in patients with DM, regardless of increased fat mass, which is called sarcopenic obesity; this effect contributes to the co-existence of a reduced Scr level and increased body weight ( 23 - 25 ). Importantly, a reduction in hemoglobin levels and elevation in BUN levels, markers of malnutrition, are not typically found at this stage of DM if patients do not have advanced-stage diabetic nephropathy.…”

“…Intriguingly, the utility of the eGFR for assessing the renal function in diabetic patients is a matter of debate ( 25 ). The results of a cross-sectional study by Luis-Lima et al showed that there was poor agreement between eGFRcre or eGFRcys and the GFR measured by the plasma clearance of iohexol (“measured GFR”), which was greater in patients with a measured GFR <60 mL/min, leading to misclassification of CKD stages in approximately 30% of the study subjects ( 26 ).…”

Vitellogenin 2 promotes muscle development and stimulates the browning of white fat

“…Many metabolic diseases, including diabetes, chronic kidney disease, and cancer, can cause whole-body muscle atrophy and make people become emaciated [ 34 , 35 ]. This situation can not only lead to the loss of body muscle mass, but also increase the mortality of humans.…”