Is Upregulation of Sarcolipin Beneficial or Detrimental to Muscle Function?

Abstract

Sarcolipin (SLN) is a regulator of sarco/endo plasmic reticulum Ca²⁺-ATPase (SERCA) pump and has been shown to be involved in muscle nonshivering thermogenesis (NST) and energy metabolism. Interestingly, SLN expression is significantly upregulated both during muscle development and in several disease states. However, the significance of altered SLN expression in muscle patho-physiology is not completely understood. We have previously shown that transgenic over-expression of SLN in skeletal muscle is not detrimental, and can promote oxidative metabolism and exercise capacity. In contrast, some studies have suggested that SLN upregulation in disease states is deleterious for muscle function and ablation of SLN can be beneficial. In this perspective article, we critically examine both published and some new data to determine the relevance of SLN expression to disease pathology. The new data presented in this paper show that SLN levels are induced in muscle during systemic bacterial (Salmonella) infection or lipopolysaccharides (LPS) treatment. We also present data showing that SLN expression is significantly upregulated in different types of muscular dystrophies including myotubular myopathy. These data taken together reveal that upregulation of SLN expression in muscle disease is progressive and increases with severity. Therefore, we suggest that increased SLN expression should not be viewed as the cause of the disease; rather, it is a compensatory response to meet the higher energy demand of the muscle. We interpret that higher SLN/SERCA ratio positively modulate cytosolic Ca²⁺ signaling pathways to promote mitochondrial biogenesis and oxidative metabolism to meet higher energy demand in muscle.

Keywords: Ca2+-handling proteins; muscle disease; sarco/endo plasmic reticulum Ca2+ ATPase; sarcolipin; skeletal muscle.

Figure 1

Sarcolipin (SLN) expression is upregulated in muscles in multiple disease states. (A) Representative western blots showing upregulation of SLN in extensor digitorum longus (EDL) and diaphragm muscles in Utrophin-dystrophin double knockout (DKO) mouse. Western blotting was performed using standard procedure as described before (Pant et al., 2015a). (B) Facioscapulohumeral muscular dystrophy (FSHD) region gene 1 (FRG1)-overexpression mice exhibit SLN upregulation in an age-dependent manner. FRG1-overexpression, wild-type, diaphragm, tibialis anterior, and trapezius are abbreviated as FR, WT, Diap, TA, and Trap, respectively. SLN upregulation increases with disease progression, whereas expression of SERCA1a, SERCA2a, and calsequestrin (CASQ) are not significantly affected. Methods for western blotting to detect the above proteins have been previously published by us (Gupta et al., 2009; Bal et al., 2012). (C) Muscles of myotubular myopathy 1 knock-in (MTM-KI) mice exhibit upregulation of SLN in an age-dependent manner. Age (in weeks) of mice studied is shown as numbers on the top of the western blots. MTM-KI is labeled as “KI.” Expression of SERCA1a and SERCA2a is unaltered. (D) Lipopolysaccharide (LPS) treatment cause fever in mice and lead to SLN upregulation in several muscles. Representative images from different western blots are pooled together. Expression of SERCA1a, SERCA2a, and CASQ1 are not altered. Muscle labeled as “Back” consists of several muscle groups from lower back portion of the mice. (E) Salmonella infection upregulate SLN expression in quadriceps muscle of WT mice and in soleus muscle of interleukin (IL) 10^−/− mice littermates. Control mice are labeled as C1 and C2. Mice infected with Salmonella are labeled as I1 and I2. TA, tibialis anterior; EDL, extensor digitorum longus; Trap, trapezius; Quad, quadriceps.

Figure 2

High SLN levels increase oxidative metabolism in the skeletal muscle. sarco/endo plasmic reticulum Ca²⁺-ATPase (SERCA) pump couples ATP hydrolysis to Ca²⁺ transport (1 ATP = 2 Ca²⁺) but this coupling is altered by SLN interaction with SERCA. When SLN is low or absent, SERCA efficiency is higher and no ATP is wasted, leading to lower energy demand. When SLN is abundant, it uncouples SERCA from Ca²⁺ transport causing futile cycling of SERCA and higher amount of ATP hydrolyzed, thus increasing the energy demand. At the same token, uncoupling of SERCA by SLN leads to elevation of cytosolic Ca²⁺ and ADP levels, both are strong activators of mitochondrial ATP synthesis, thereby helping in meeting the increased metabolic demand. Enhanced SLN activity plays an important role in muscle adaptation to high energy demand/expenditure such as cold/diet induced thermogenesis and endurance exercise that relies on mitochondrial oxidative metabolism. In addition, higher SLN expression/activity is beneficial to meet the increased energy demand in structurally compromised dystrophic muscles. MCU, mitochondrial uniporter; ETC, electron transport chain; VDAC, voltage dependent anion channel.