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Review
. 2018 Dec;12(4):645-659.
doi: 10.1007/s12079-018-0477-z. Epub 2018 Jul 7.

Role of defective Ca2+ signaling in skeletal muscle weakness: Pharmacological implications

Akanksha Agrawal  1 , Geetha Suryakumar  1 , Richa Rathor  2
Affiliations
Review

Role of defective Ca2+ signaling in skeletal muscle weakness: Pharmacological implications

Akanksha Agrawal et al. J Cell Commun Signal. 2018 Dec.

Abstract

The misbehaving attitude of Ca2+ signaling pathways could be the probable reason in many muscular disorders such as myopathies, systemic disorders like hypoxia, sepsis, cachexia, sarcopenia, heart failure, and dystrophy. The present review throws light upon the calcium flux regulating signaling channels like ryanodine receptor complex (RyR1), SERCA (Sarco-endoplasmic Reticulum Calcium ATPase), DHPR (Dihydropyridine Receptor) or Cav1.1 and Na+/Ca2+ exchange pump in detail and how remodelling of these channels contribute towards disturbed calcium homeostasis. Understanding these pathways will further provide an insight for establishing new therapeutic approaches for the prevention and treatment of muscle atrophy under stress conditions, targeting calcium ion channels and associated regulatory proteins.

Keywords: Atrophy; Calcium; Muscle; RyR1; Ryanodine receptor.

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Conflict of interest statement

No conflicts of interest, financial or otherwise, are declared by the author(s).

Figures

Fig. 1
Fig. 1
Schematic representation of the different diseases involved in causing muscle dystrophy and changes occur in muscle fibres which may finally lead to muscle degeneration
Fig. 2
Fig. 2
Stress responses in skeletal muscle during E-C coupling. Depolarization of the T-tubule membrane activates Cav1.1, triggering SR Ca2+ release through RyR1 and leading to sarcomere contraction, a process known as E-C coupling. During pathological stress intracellular signaling pathways activated and affect RyR1 function and alter E-C coupling. Stress-induced RyR1 dysfunction can result in SR Ca2+ leak, which potentially activates numerous Ca2+-dependent cellular damage mechanisms. AC, adenylate cyclise; CSQ, Calsequestrin; SERCA1a, Sarcoplasmic Reticulum Calcium-ATPase; RyR1, Ryanodine receptor 1
Fig. 3
Fig. 3
A model of “leaky” RYR1 channel in pathological skeletal muscles. a RyR1 from normal skeletal muscle is not “leaky” and the sequestration of calcium ion occurred due to RYR1 activation which triggers muscle contraction b In pathological state, ROS and RNS mediated remodelling of RYR1 channel and impaired calcium homeostasis which may lead to decreased muscle force and moreover, it may lead to muscular atrophy
Fig. 4
Fig. 4
Intracellular calcium regulates muscle atrophy via calpain regulated Ub-proteasome pathway and apoptosis
Fig. 5
Fig. 5
Ca2+ sparks in smooth muscle cells. Left: local control of Ca2+ sparks. Right. Ca2+ spark activate Ca2+-K+ channel to complete negative feedback loop () and also illustrated a positive-feedback () of Ca2+ release from RyR channels to contraction
See this image and copyright information in PMC

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