Acylated ghrelin treatment normalizes skeletal muscle mitochondrial oxidative capacity and AKT phosphorylation in rat chronic heart failure

Abstract

BackgroundChronic heart failure (CHF) is associated with skeletal muscle abnormalities contributing to exercise intolerance, muscle loss, and negative impact on patient prognosis. A primary role has been proposed for mitochondrial dysfunction, which may be induced by systemic and tissue inflammation and further contribute to low insulin signalling. The acylated form of the gastric hormone ghrelin (AG) may improve mitochondrial oxidative capacity and insulin signalling in both healthy and diseased rodent models.MethodsWe investigated the impact of AG continuous subcutaneous administration (AG) by osmotic minipump (50 nmol/kg/day for 28 days) compared with placebo (P) on skeletal muscle mitochondrial enzyme activities, mitochondrial biogenesis regulators transcriptional expression and insulin signalling in a rodent post‐myocardial infarction CHF model.ResultsNo statistically significant differences (NS) were observed among the three group in cumulative food intake. Compared with sham‐operated, P had low mitochondrial enzyme activities, mitochondrial biogenesis regulators transcripts, and insulin signalling activation at AKT level (P < 0.05), associated with activating nuclear translocation of pro‐inflammatory transcription factor nuclear factor‐κB. AG completely normalized all alterations (P < 0.05 vs P, P = NS vs sham‐operated). Direct AG activities were strongly supported by in vitro C2C12 myotubes experiments showing AG‐dependent stimulation of mitochondrial enzyme activities. No changes in mitochondrial parameters and insulin signalling were observed in the liver in any group.ConclusionsSustained peripheral AG treatment with preserved food intake normalizes a CHF‐induced tissue‐specific cluster of skeletal muscle mitochondrial dysfunction, pro‐inflammatory changes, and reduced insulin signalling. AG is therefore a potential treatment for CHF‐associated muscle catabolic alterations, with potential positive impact on patient outcome.

Skeletal muscle wasting in chronic heart failure

“…Unfortunately, because of a lack of consensus on the definition of sarcopenia, there are problems with its definite detection. 34 In addition, a sarcopenia-specific Quality of Life questionnaire has recently been introduced. [41][42][43] As a result, the definition of sarcopenia (two standard deviations of normal muscle mass) has been modified to contain measurements of impaired physical function, such as slow walking speed and low grip strength.…”

“…wasting of myofibrillar proteins, of the diaphragm and quadriceps muscles have been observed. 34 Another contributing factor to sarcopenia is a variable degree of malnutrition 56 that may be caused by inflammatory cytokines, 57-59 which have been known to contribute to anorexia in chronic disease. 53,54 Skeletal muscle density has been suggested to be an independent marker of clinical outcome.…”

“…To circumvent the potential severe side effects of testosterone, selective androgen receptor modulators like enobosarm have been developed, which have similar anabolic effects to testosterone, but are believed to have fewer severe side effects. 34 Myostatin (also known as GDF-8) is a negative regulator of muscle mass, which binds primarily to the activin II B receptor. 101 Recently, urolithin B, an ellagitannin-derived metabolite, has been observed to have beneficial effects on skeletal muscle growth by involving the androgen receptor in C2C12 myotubes and a mouse model of denervation.…”

“…25,33 In contrast to cachexia, sarcopenia and muscle wasting cannot be identified by simply longitudinally determining the patients' body weight to detect involuntary weight loss. 34,35 Sarcopenia affects 5-13% of elderly persons aged 60-70 years and up to 50% of all octogenarians. 36 The prevalence of sarcopenia in Asia ranges from 4.1% to 11.5% of the general older population.…”

Metabolic disorders in heart failure and cancer

“…16,17 Once heart failure develops it is associated with high 5-year mortality rates of 50% or more. 58,59 These rather new areas of research are a common problem in chronic diseases, gaining growing attention from the scientific community. 21,22 Unfortunately major randomized controlled trials in both conditions usually list the other as an exclusion criterion, so that we have less trial evidence of the interaction between HF and cancer.…”