Abstract
Hyperhomocysteinemia (HHcy) is a systemic medical condition and has been attributed to multi-organ pathologies. Genetic, nutritional, hormonal, age and gender differences are involved in abnormal homocysteine (Hcy) metabolism that produces HHcy. Homocysteine is an intermediate for many key processes such as cellular methylation and cellular antioxidant potential and imbalances in Hcy production and/or catabolism impacts gene expression and cell signaling including GPCR signaling. Furthermore, HHcy might damage the vagus nerve and superior cervical ganglion and affects various GPCR functions; therefore it can impair both the parasympathetic and sympathetic regulation in the blood vessels of skeletal muscle and affect long-term muscle function. Understanding cellular targets of Hcy during HHcy in different contexts and its role either as a primary risk factor or as an aggravator of certain disease conditions would provide better interventions. In this review we have provided recent Hcy mediated mechanistic insights into different diseases and presented potential implications in the context of reduced muscle function and integrity. Overall, the impact of HHcy in various skeletal muscle malfunctions is underappreciated; future studies in this area will provide deeper insights and improve our understanding of the association between HHcy and diminished physical function.
Highlights
Hyperhomocysteinemia (HHcy) is a metabolic systemic disorder with defects in sulphur-containing amino acid metabolism leading to abnormally higher amounts of non-building-block intermediary amino acid homocysteine (Hcy)
Normal levels of Hcy in the blood range from 10 to 12 μM and in very severe cases the concentrations might shoot above 100 μM, which leads to homocystinuria
Homocysteine is synthesized from methionine (Figure 1), absorbed from the digestive system, by a process called demethylation that involves the generation of S-adenosylmethionine (SAM) and
Summary
Hyperhomocysteinemia (HHcy) is a metabolic systemic disorder with defects in sulphur-containing amino acid (methionine and cysteine) metabolism leading to abnormally higher amounts of non-building-block intermediary amino acid homocysteine (Hcy). In the cases of mutant CBS and CST presence, HHcy could further aggravate the cellular oxidative stress by competitively inhibiting the cysteine uptake by the cells Consistent with this hypothesis, dietary cysteine depletion in mice carrying deficient cystathionine γ-lyase (CTH) activity (another key enzyme in the transsulfuration process and expressed in human skeletal muscles [23]) resulted in reduced glutathione content in skeletal muscles, enhanced sensitivity to oxidative stress, and lethal muscular atrophy [28]. Understanding global changes in gene expression owing to altered DNA methylation in the presence of disease relevant doses of Hcy would provide a framework for comprehensive delineation of HHcy mediated skeletal muscle damage. Given that SAH can inhibit the cellular methylation reactions [1], HHcy may potentially limit the liver supply of creatine and may reduce muscle endurance and enhance muscle damage. Whether HHcy affects the ER function to cause diminished muscle performance is currently unknown
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
