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Role of SERCA Pump in Muscle Thermogenesis and Metabolism

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ABSTRACT

In muscle cells, the sarcoplasmic reticulum (SR) not only acts as a Ca2+ store, but also regulates the contractile characteristics of the muscle. Ca2+ release from the SR is the primary mechanism for activating muscle contraction and reuptake of Ca2+ by the sarcoplasmic reticulum Ca2+ ATPase (SERCA) pump causes muscle relaxation. The SERCA pump isoforms are encoded by three genes, SERCA 1, 2, and 3, which are differentially expressed in muscle and determine SR Ca2+ dynamics by affecting the rate and amount of Ca2+ uptake, thereby affecting SR store and release of Ca2+ in muscle. In muscle, small molecular weight proteins, including Phospholamban (PLB) and Sarcolipin (SLN), also regulate the SERCA pump. Regulation of the SERCA pump by PLB or SLN affects cytosolic Ca2+ dynamics and changes in cytosolic Ca2+ not only affect contractile function, but also mitochondrial ATP production. Recent studies have shown that alterations in cytosolic Ca2+ affects Ca2+ entry into mitochondria and ATP production; thus, Ca2+ serves as an integrating signal between muscle contraction‐dependent energy demand and mitochondrial energy production. In addition, changes in cytosolic Ca2+ can affect Ca2+ signaling pathways modulating gene expression and muscle growth. An emerging area of research shows that SR Ca2+ cycling is also a player in muscle‐based nonshivering thermogenesis. Recent data shows that SERCA uncoupling by SLN leads to increased ATP hydrolysis and heat production. Our studies, using genetically altered mouse models of SLN, show that SLN/SERCA interaction plays an important role in muscle thermogenesis and metabolism, which will be discussed here, in great length. © 2017 American Physiological Society. Compr Physiol 7:879‐890, 2017.

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Figure 1. Figure 1. The role of sarcoplasmic reticulum in muscle excitation‐contraction coupling. The SR in muscle is a highly specialized organelle and serves as a Ca2+ store. Ca2+ release and uptake by the SR is primarily responsible for contraction and relaxation of the muscle. The major SR Ca2+ cycling proteins include the Ca2+ release channel also known as ryanodine receptor (RYR), SERCA pump, Na+/Ca2+ exchanger, and voltage gated L‐type Ca2+ channel. These proteins regulate Ca2+ release and removal during muscle contraction and relaxation (). The SERCA pump isotype and relative protein content is an important determinant of SR Ca2+ load, release, and uptake in fast‐twitch (SERCA1a) versus slow‐twitch (SERCA2a) muscle. The SR and mitochondria are interdependent and changes in cytosolic Ca2+ can also affect mitochondrial energetics.
Figure 2. Figure 2. Comparison of SLN, DWORF, MLN, and PLB protein sequences in mouse. SLN is 31 AA long with 7 unique cytosolic residues and a highly conserved C‐terminus (RSYQY) across different species including humans and rodents. These proteins share homology only in the transmembrane region but have unique cytosolic and lumenal residues. PLB is the largest, it is 52 AA long, and has an extended cytosolic domain of 30 AA containing phosphorylation sites at Ser16 and Thr17(74). The mechanism of interaction with SERCA has been extensively studied for PLB and SLN but the details regarding DWORF and MLN interaction are not known.
Figure 3. Figure 3. Distinct interaction and regulation of SERCA by SLN and PLB. SLN and PLB binding to SERCA as detected by protein cross‐linking in the presence of different concentration of Ca2+. (A) SLN is able to bind to SERCA even at high Ca2+ whereas PLB binding to SERCA is competed out by increasing Ca2+, indicating that binding of PLB and Ca2+ are mutually exclusive. (B) SLN remains bound to SERCA pump during Ca2+ transport (binds to different SERCA kinetic states, that is, E2, E1, E1pCa2, and E2P) and PLB only binds to Ca2+ free SERCA pump (). (C) Ca2+ uptake assay profile shows that SLN decreases the Vmax of SERCA Ca2+ transport by uncoupling. (D) SLN does not inhibit SERCA ATPase activity. PLB inhibits SERCA ATPase activity but has no effect on Vmax of Ca2+ uptake. Adapted from Sahoo et al. JBC ().
Figure 4. Figure 4. SLN plays a role in muscle thermogenesis. (A) Infrared imaging of surface body heat in WT and Sln−/− mice with or without iBAT at 22°C and 4°C. (B) Core body temperature after acute cold exposure in WT and Sln−/− mice, with and without iBAT. (C) Percentage of mice reaching ERC (early removal criteria) (10). The mice were removed from cold when body Tc reached 25°C. All data are means ± S.E.M. Adapted from Bal et al. Nat Medicine ().
Figure 5. Figure 5. SLN plays an important role in whole body metabolism and obesity. Mice were fed on HFD for 12 weeks. (A and B) SLN‐/‐ mice show significant increase in body weight. (C) MRI images showing body fat distribution in WT and Sln−/− after high fat diet feeding. (D) SLN protein level is increased in HFD‐fed WT–Soleus. n = 4. (E) Overexpression of SLN provides resistance against diet induced obesity. (F) SlnOE mice consumed more calories than WT during HFD feeding. All data are means ± S.E.M. Adapted from Bal et al. Nat Medicine and Maurya et al. JBC ().
Figure 6. Figure 6. Proposed model showing how SLN/SERCA interaction leads to increased mitochondrial biogenesis and oxidative metabolism. SERCA uses ATP hydrolysis to actively transport Ca2+ from the cytosol into the sarcoplasmic reticulum lumen. SLN binding to SERCA causes uncoupling of Ca2+ transport from ATP hydrolysis. Uncoupling of SERCA leads to futile cycling of the pump and increased ATP hydrolysis/heat production, thereby creating energy demand. Decreased SERCA mediated Ca2+ uptake increases the cytosolic Ca2+, which promotes Ca2+ entry into mitochondria, activating mitochondrial oxidative metabolism and ATP synthesis. An increase in cytosolic Ca2+ leads to activation of Ca2+‐dependent signaling pathways and nuclear transcription factors PGC1α, and PPARδ promoting mitochondrial biogenesis. CRU, calcium release unit.


Figure 1. The role of sarcoplasmic reticulum in muscle excitation‐contraction coupling. The SR in muscle is a highly specialized organelle and serves as a Ca2+ store. Ca2+ release and uptake by the SR is primarily responsible for contraction and relaxation of the muscle. The major SR Ca2+ cycling proteins include the Ca2+ release channel also known as ryanodine receptor (RYR), SERCA pump, Na+/Ca2+ exchanger, and voltage gated L‐type Ca2+ channel. These proteins regulate Ca2+ release and removal during muscle contraction and relaxation (). The SERCA pump isotype and relative protein content is an important determinant of SR Ca2+ load, release, and uptake in fast‐twitch (SERCA1a) versus slow‐twitch (SERCA2a) muscle. The SR and mitochondria are interdependent and changes in cytosolic Ca2+ can also affect mitochondrial energetics.


Figure 2. Comparison of SLN, DWORF, MLN, and PLB protein sequences in mouse. SLN is 31 AA long with 7 unique cytosolic residues and a highly conserved C‐terminus (RSYQY) across different species including humans and rodents. These proteins share homology only in the transmembrane region but have unique cytosolic and lumenal residues. PLB is the largest, it is 52 AA long, and has an extended cytosolic domain of 30 AA containing phosphorylation sites at Ser16 and Thr17(74). The mechanism of interaction with SERCA has been extensively studied for PLB and SLN but the details regarding DWORF and MLN interaction are not known.


Figure 3. Distinct interaction and regulation of SERCA by SLN and PLB. SLN and PLB binding to SERCA as detected by protein cross‐linking in the presence of different concentration of Ca2+. (A) SLN is able to bind to SERCA even at high Ca2+ whereas PLB binding to SERCA is competed out by increasing Ca2+, indicating that binding of PLB and Ca2+ are mutually exclusive. (B) SLN remains bound to SERCA pump during Ca2+ transport (binds to different SERCA kinetic states, that is, E2, E1, E1pCa2, and E2P) and PLB only binds to Ca2+ free SERCA pump (). (C) Ca2+ uptake assay profile shows that SLN decreases the Vmax of SERCA Ca2+ transport by uncoupling. (D) SLN does not inhibit SERCA ATPase activity. PLB inhibits SERCA ATPase activity but has no effect on Vmax of Ca2+ uptake. Adapted from Sahoo et al. JBC ().


Figure 4. SLN plays a role in muscle thermogenesis. (A) Infrared imaging of surface body heat in WT and Sln−/− mice with or without iBAT at 22°C and 4°C. (B) Core body temperature after acute cold exposure in WT and Sln−/− mice, with and without iBAT. (C) Percentage of mice reaching ERC (early removal criteria) (10). The mice were removed from cold when body Tc reached 25°C. All data are means ± S.E.M. Adapted from Bal et al. Nat Medicine ().


Figure 5. SLN plays an important role in whole body metabolism and obesity. Mice were fed on HFD for 12 weeks. (A and B) SLN‐/‐ mice show significant increase in body weight. (C) MRI images showing body fat distribution in WT and Sln−/− after high fat diet feeding. (D) SLN protein level is increased in HFD‐fed WT–Soleus. n = 4. (E) Overexpression of SLN provides resistance against diet induced obesity. (F) SlnOE mice consumed more calories than WT during HFD feeding. All data are means ± S.E.M. Adapted from Bal et al. Nat Medicine and Maurya et al. JBC ().


Figure 6. Proposed model showing how SLN/SERCA interaction leads to increased mitochondrial biogenesis and oxidative metabolism. SERCA uses ATP hydrolysis to actively transport Ca2+ from the cytosol into the sarcoplasmic reticulum lumen. SLN binding to SERCA causes uncoupling of Ca2+ transport from ATP hydrolysis. Uncoupling of SERCA leads to futile cycling of the pump and increased ATP hydrolysis/heat production, thereby creating energy demand. Decreased SERCA mediated Ca2+ uptake increases the cytosolic Ca2+, which promotes Ca2+ entry into mitochondria, activating mitochondrial oxidative metabolism and ATP synthesis. An increase in cytosolic Ca2+ leads to activation of Ca2+‐dependent signaling pathways and nuclear transcription factors PGC1α, and PPARδ promoting mitochondrial biogenesis. CRU, calcium release unit.
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Muthu Periasamy, Santosh Kumar Maurya, Sanjaya Kumar Sahoo, Sushant Singh, Felipe C. G. Reis, Naresh Chandra Bal. Role of SERCA Pump in Muscle Thermogenesis and Metabolism. Compr Physiol 2017, 7: 879-890. doi: 10.1002/cphy.c160030