Calcium Homeostasis Is Altered in Skeletal Muscle of Spontaneously Hypertensive Rats

Abstract

Hypertension is often associated with skeletal muscle pathological conditions related to function and metabolism. The mechanisms underlying the development of these pathological conditions remain undefined. Because calcium homeostasis is a biomarker of muscle function, we assessed whether it is altered in hypertensive muscles. We measured resting intracellular calcium and store-operated calcium entry (SOCE) in fast- and slow-twitch muscle fibers from normotensive Wistar-Kyoto rats and spontaneously hypertensive rats (SHRs) by cytofluorimetric technique and determined the expression of SOCE gene machinery by real-time PCR. Hypertension caused a phenotype-dependent dysregulation of calcium homeostasis; the resting intracellular calcium of extensor digitorum longus and soleus muscles of SHRs were differently altered with respect to the related muscle of normotensive animals. In addition, soleus muscles of SHR showed reduced activity of the sarcoplasmic reticulum and decreased sarcolemmal calcium permeability at rest and after SOCE activation. Accordingly, we found an alteration of the expression levels of some SOCE components, such as stromal interaction molecule 1, calcium release-activated calcium modulator 1, and transient receptor potential canonical 1. The hypertension-induced alterations of calcium homeostasis in the soleus muscle of SHRs occurred with changes of some functional outcomes as excitability and resting chloride conductance. We provide suitable targets for therapeutic interventions aimed at counterbalancing muscle performance decline in hypertension, and propose the reported calcium-dependent parameters as indexes to predict how the antihypertensive drugs could influence muscle function.

Growth hormone secretagogues prevent dysregulation of skeletal muscle calcium homeostasis in a rat model of cisplatin‐induced cachexia

“…In line with previous studies, EDL fast‐twitch skeletal muscle fibres of adult control rats showed a value of resting [Ca 2+ ] i of 29.7 ± 1.9 nM. Cisplatin administration was associated with a significant alteration of resting [Ca 2+ ] i .…”

“…To test the functional status of SOCE in muscles of the different animal groups, we used Mn 2+ quenching of Fura‐2 fluorescence after SOCE activation. To this end, SR Ca 2+ stores of muscle fibres were depleted with thapsigargin and caffeine . As shown in Figure A and 5B, EDL muscle of cisplatin treated rats displays a significantly reduced Mn 2+ entry rate compared with that of control animal, indicating that SOCE induced by SR Ca 2+ depletion is compromised in cachectic muscle.…”

“…and caffeine. 13,43 As shown in Figure 5A and 5B, EDL muscle of cisplatin treated rats displays a significantly reduced Mn 2+ entry rate compared with that of control animal, indicating that SOCE induced by SR Ca 2+ depletion is compromised in cachectic muscle. Both GHS fully prevented the SOCE decrease ( Figure 5B).…”

“…The solution was incubated at 50°C for 2 min, 95°C for 10 min and for 40 cycles of 95°C for 15 s and 60°C for 1 min. The methods of gene expression analysis are the same as those previously used . The RT‐PCR experiments were performed in agreement with the MIQE guidelines for qPCR …”

“…It is known that abnormal intracellular free Ca 2+ concentration causes disruption of normal excitation‐contraction (EC) coupling; it can also stimulate the activity of various enzymes, such as calpains, phospholipase A 2 or protein kinase C and can activate various transcription factors . Accordingly, a clear link has been found between calcium homeostasis alteration and muscle performance decline observed in various pathophysiological conditions affecting skeletal muscle such as ageing, disuse, hypertension, muscular dystrophy or in states of drug‐induced muscle toxicity . It has been demonstrated that several genes that are decreased in extensor digitorum longus (EDL) muscle of cachectic rats encode for proteins that have the ability to bind Ca 2+ and therefore to affect EC coupling .…”