Lack of β ₂-adrenoceptors aggravates heart failure-induced skeletal muscle myopathy in mice

Abstract

Skeletal myopathy is a hallmark of heart failure (HF) and has been associated with a poor prognosis. HF and other chronic degenerative diseases share a common feature of a stressed system: sympathetic hyperactivity. Although beneficial acutely, chronic sympathetic hyperactivity is one of the main triggers of skeletal myopathy in HF. Considering that β ₂-adrenoceptors mediate the activity of sympathetic nervous system in skeletal muscle, we presently evaluated the contribution of β ₂-adrenoceptors for the morphofunctional alterations in skeletal muscle and also for exercise intolerance induced by HF. Male WT and β ₂-adrenoceptor knockout mice on a FVB genetic background (β ₂KO) were submitted to myocardial infarction (MI) or SHAM surgery. Ninety days after MI both WT and β ₂KO mice presented to cardiac dysfunction and remodelling accompanied by significantly increased norepinephrine and epinephrine plasma levels, exercise intolerance, changes towards more glycolytic fibres and vascular rarefaction in plantaris muscle. However, β ₂KO MI mice displayed more pronounced exercise intolerance and skeletal myopathy when compared to WT MI mice. Skeletal muscle atrophy of infarcted β ₂KO mice was paralleled by reduced levels of phosphorylated Akt at Ser 473 while increased levels of proteins related with the ubiquitin-–proteasome system, and increased 26S proteasome activity. Taken together, our results suggest that lack of β ₂-adrenoceptors worsen and/or anticipate the skeletal myopathy observed in HF.