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Lack of ?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 ?2 -adrenoceptors mediate the activity of sympathetic nervous system in skeletal muscle, we presently evaluated the contribution of ?2 -adrenoceptors for the morphofunctional alterations in skeletal muscle and also for exercise intolerance induced by HF. Male WT and ?2 -adrenoceptor knockout mice on a FVB genetic background (?2 KO) were submitted to myocardial infarction (MI) or SHAM surgery. Ninety days after MI both WT and ?2 KO 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, ?2 KO MI mice displayed more pronounced exercise intolerance and skeletal myopathy when compared to WT MI mice. Skeletal muscle atrophy of infarcted ?2 KO 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 ?2 -adrenoceptors worsen and/or anticipate the skeletal myopathy observed in HF.

SUBMITTER: Voltarelli VA

PROVIDER: S-EPMC4508148 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Lack of β2 -adrenoceptors aggravates heart failure-induced skeletal muscle myopathy in mice.

Voltarelli Vanessa A VA Bechara Luiz R G LR Bacurau Aline V N AV Mattos Katt C KC Dourado Paulo M M PM Bueno Carlos R CR Casarini Dulce E DE Negrao Carlos E CE Brum Patricia C PC

Journal of cellular and molecular medicine 20140313 6

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 β2 -adrenoceptors mediate the activity of sympathetic nervous system in skeletal muscle, we presently evaluated the contribution of β2 -adrenoceptor ...[more]

PMID: 24629015

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Project description:BACKGROUND:Skeletal muscle myopathy and exercise intolerance are diagnostic hallmarks of heart failure (HF). However, the molecular adaptations of skeletal muscles during dilated cardiomyopathy (DCM)-mediated HF are not completely understood. METHODS:Skeletal muscle structure and function were compared in wild-type (WT) and cardiac myosin binding protein-C null mice (t/t), which develop DCM-induced HF. Cardiac function was examined by echocardiography. Exercise tolerance was measured using a graded maximum treadmill running test. Hindlimb muscle function was assessed in vivo from measurements of plantar flexor strength. Inflammatory status was evaluated from the expression of inflammatory markers and the presence of specific immune cell types in gastrocnemius muscles. Muscle regenerative capacityat days 3, 7, and 14 after eccentric contraction-induced injury was determined from the number of phenotypically new and adult fibers in the gastrocnemius, and functional recovery of plantar flexion torque. RESULTS:t/t mice developed DCM-induced HF in association with profound exercise intolerance, consistent with previous reports. Compared to WT, t/t mouse hearts show significant hypertrophy of the atria and ventricles and reduced fractional shortening, both systolic and diastolic. In parallel, the skeletal muscles of t/t mice exhibit weakness and myopathy. Compared to WT, plantar flexor muscles of t/t null mice produce less peak isometric plantar torque (Po), develop torque more slowly (+?dF/dt), and relax more slowly (-?dF/dt, longer half-relaxation times,1/2RT). Gastrocnemius muscles of t/t mice have a greater number of fibers with smaller diameters and central nuclei. Oxidative fibers, both type I and type IIa, show significantly smaller cross-sectional areas and more central nuclei. These fiber phenotypes suggest ongoing repair and regeneration under homeostatic conditions. In addition, the ability of muscles to recover and regenerate after acute injury is impaired in t/t mice. CONCLUSIONS:Our studies concluded that DCM-induced HF induces a unique skeletal myopathy characterized by decreased muscle strength, atrophy of oxidative fiber types, ongoing inflammation and damage under homeostasis, and impaired regeneration after acute muscle injury. Furthermore, this unique myopathy in DCM-induced HF likely contributes to and exacerbates exercise intolerance. Therefore, efforts to develop therapeutic interventions to treat skeletal myopathy during DCM-induced HF should be considered.

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

Publications

Lack of β2 -adrenoceptors aggravates heart failure-induced skeletal muscle myopathy in mice.

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