Hyperhomocysteinemia associated skeletal muscle weakness involves mitochondrial dysfunction and epigenetic...

Area of Science:

• Muscle physiology and mitochondrial biology
• Epigenetics and molecular mechanisms of disease
• Aging and frailty research

Background:

• High homocysteine (HHcy) is linked to elderly frailty, but its molecular basis in skeletal muscle remains unclear.
• Understanding HHcy's impact on muscle function is crucial for developing interventions against age-related weakness.

Purpose of the Study:

• To investigate the mechanisms by which HHcy induces skeletal muscle weakness and fatigability.
• To examine the role of metabolic capacity, structural proteins, and mitochondrial function in HHcy-induced muscle dysfunction.
• To assess the potential of exercise to reverse HHcy-related molecular and functional changes in muscle.

Main Methods:

• Utilized C57 mice, CBS+/- mice, and C2C12 myoblast cell line.
• Assessed muscle fatigability, contraction force, and key metabolic enzymes (LDH, CS, MM-CK, COX-IV).
• Analyzed ATP production, dystrophin levels, mitochondrial transcription factor A (mtTFA), and associated microRNAs (mir-31, mir-494).
• Investigated epigenetic modifications including DNA methylation and associated enzymes (DNMT3a, DNMT3b).
• Implemented an exercise regimen to evaluate its reversal effects on HHcy-induced changes.

Main Results:

• CBS+/- mice showed increased fatigability and reduced contraction force, linked to lower ATP levels, not altered metabolic enzymes.
• Marginal decreases in dystrophin and mtTFA were observed, accompanied by increased mir-31 and mir-494.
• Exercise partially reversed molecular changes, except for dystrophin levels.
• Homocysteine treatment in C2C12 cells led to reduced mtTFA, increased mir-494, elevated DNMT3a/3b, and increased global DNA methylation.
• NRF-1, a transcriptional regulator of mtTFA, was significantly decreased.

Conclusions:

• HHcy contributes causally to muscle fatigability primarily through mitochondrial dysfunction.
• Epigenetic alterations, including DNA methylation changes, play a significant role in HHcy-induced mitochondrial dysfunction and muscle weakness.
• Exercise demonstrates a partial capacity to ameliorate HHcy-induced molecular deficits in skeletal muscle.