Regulation of skeletal muscle free intracellular calcium, force generation and fatigue resistance by second messengers derived from NAD

• Grant number: 19/16891-8
• Support Opportunities: Regular Research Grants
• Duration: February 01, 2021 - January 31, 2024
• Field of knowledge: Health Sciences - Physical Education
• Principal Investigator: Paulo Guimarães Gandra
• Grantee: Paulo Guimarães Gandra
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

Calcium ions are central for excitation-contraction coupling in skeletal muscle. A new mechanism proposed to regulate skeletal muscle Ca2+-handling is the generation of Ca2++mobilizing messengers derived from NAD, such as ADP-ribose (ADPR) and cyclic ADP-ribose (cADPR). Different studies have shown that: cADPR generation is increased in muscle during exercise; that cADPR can increase free intracellular [Ca2+] ([Ca2+]i) and activate the sarcoplasmic reticulum calcium pump (SERCA); an increased SERCA activity in skeletal muscle can enhance exercise capacity; increases in [Ca2+]i during prolonged muscle stimulation can impair muscle contractility during recovery from fatigue. However, it is still unclear: what are the roles of ADPR in skeletal muscle; the importance of cADPR for muscle function during fatigue; if NAD+ precursors (used to treat different pathologies) can affect [Ca2+]i in skeletal muscle; if the pharmacological activation of SERCA can improve muscle function after fatigue. We will test the hypothesis: 1) that endogenous ADPR and cADPR are important to regulate muscle function; 2) that the treatment with a NAD precursor can affect [Ca2+]i in skeletal muscle; 3) that the treatment with a new small molecule activator of SERCA can improve muscle function during and after fatigue development. To answer these questions we will use an isolated intact single fiber model that allows the simultaneous measurement of force generation and [Ca2+]i by fluorescence microscopy during stimulation. These studies will bring new information regarding the cellular mechanisms regulating muscle [Ca2+]i and contractility during stimulation that may be important for the development of new strategies to improve muscle function and exercise tolerance. (AU)