Phosphodiesterases S-sulfhydration contributes to human skeletal muscle function.

Area of Science:

• Muscle physiology and pathophysiology
• Biochemistry and molecular biology
• Skeletal muscle (SKM) research

Background:

• Intracellular calcium levels are regulated by cyclic nucleotides (cAMP, cGMP) and phosphodiesterases (PDEs).
• The role of the cAMP-cGMP/PDEs axis in human SKM contractility is not fully understood.
• Hydrogen sulfide (H2S) overproduction contributes to hyper-contractility in Malignant Hyperthermia (MH).

Purpose of the Study:

• To investigate the role of S-sulfhydration of PDEs in human SKM contractility.
• To explore the impact of H2S on PDE activity and cyclic nucleotide levels in physiological and pathological conditions.
• To elucidate the novel post-translational modification (PTM) of PDEs in SKM.

Main Methods:

• Utilized MH negative (MHN) biopsies as healthy controls and MH susceptible (MHS) biopsies as a model for SKM hypercontractility.
• Analyzed primary SKM cells derived from both MHN and MHS biopsies.
• Assessed S-sulfhydration status of PDEs and cyclic nucleotide levels (cAMP, cGMP).

Main Results:

• PDEs are S-sulfhydrated in normal human SKM, negatively regulating their activity and increasing cAMP/cGMP levels.
• In hypercontractile MHS biopsies, excessive H2S leads to enhanced PDE S-sulfhydration.
• This enhanced S-sulfhydration further elevates cyclic nucleotide levels, contributing to SKM hyper-contractility.

Conclusions:

• S-sulfhydration is a novel endogenous PTM that modulates PDE activity in human SKM.
• This PTM plays a significant role in regulating SKM contractility under both physiological and pathological conditions.
• Understanding this mechanism advances the comprehension of SKM physiopathology, particularly in conditions like MH.