SRP-35, a newly identified skeletal muscle protein linking excitation-contraction coupling to activation of metabolism

Prof. Susan Treves, University of Basel, Dept. Biomedicine


Skeletal muscle constitutes approximately 50% of the body mass and plays an important role in human health, in fact lack of skeletal muscle exercise has been linked to chronic diseases such as hypertension, obesity and diabetes (1). Furthermore, skeletal muscle is responsible for approximately 80% of insulin-stimulated glucose uptake being a key tissue involved in glucose homeostasis and in fatty acid catabolism (2). In striated muscle, activation of contraction is initiated by membrane depolarisation during an action potential, which causes release of Ca2+ from the sarcoplasmic reticulum, by a process called excitation-contraction (E-C) coupling (3,4). Defects in E-C coupling and/or Ca2+ dysregulation are the underlying feature of several neuromuscular disorders. Though contraction and relaxation of myofilaments involves short-term Ca2+ signalling events occurring within milliseconds, Ca2+ signalling can also regulate slower events such as transcription, via activation the Ca2+ sensitive transcription factors such as NFAT (5,6) an event that, at variance from excitation-contraction, occurs over long periods of time (hours to days). In addition, increases in [Ca2+] also affect metabolism either directly (for example by signalling to mitochondria) or indirectly, by generating secondary signalling molecules or metabolic bi-products (ex NADH). 

In order to find molecular link(s) coupling excitation-contraction to metabolic activation it is important to (i) identify the full complement of protein components of the excitation-contraction coupling machinery and define their functional role and (ii) investigate if such proteins play a role in metabolism, for example by stimulating glucose uptake, by affecting gene transcription, by activating fatty acid metabolism etc. Furthermore, we think the precise definition of the roles of all proteins involved in E-C coupling is important in order to understand how their changes cause neuromuscular disorders.

The aim of this project is to investigate in detail the functional role of SRP-35, a 35 kDa a retinol dehydrogenase we recently identified in skeletal muscle sarcoplasmic reticulum. Based on our findings, we hypothesise that SRP-35 may link contraction to the activation of muscle metabolism. SRP-35 protein belongs to the “Short Chain Dehydrogenase/Reductase” family. The enzymatic activity of SRP-35 is coupled to the reduction of NAD(P)+ to NADH(P) and mediates the conversion of  retinol to retinaldehyde. The irreversible oxidation of retinaldehyde by dehydrogenases leads to the formation of retinoic acid. Retinoic acid is known to regulate gene expression by activating the ligand-modulated transcription factors RA receptors (RAR) and rexinoid receptors (RXR receptors). RAR:RXR heterodimers control the expression of retinoid target genes (2, 7) and interestingly, retinoic acid has been shown to increase lipid oxidation capacity of skeletal muscle (2). This study will offer important insight into the identification of molecular components coupling muscle activity to metabolism under normal conditions and may shed light on the identification of potential molecular targets for the treatment of age-associated dismetabolic disorders such as type 2 diabetes.