Heme Metabolism-Derived Carbon Monoxide Regulates Skeletal Muscle Function

Area of Science:

• Muscle Physiology
• Mitochondrial Biology
• Neuromuscular Plasticity

Background:

• Heme oxygenases (HO-1 and HO-2) are critical for skeletal muscle homeostasis, regulating heme degradation and producing carbon monoxide (CO).
• While HO-1's role in muscle fiber composition and mitochondrial function is known, HO-2's contribution to activity-dependent neuromuscular plasticity is less understood.
• This study investigates the distinct roles of HO-1 and HO-2 and the potential of CO to ameliorate muscle dysfunction in HO-deficient models.

Purpose of the Study:

• To elucidate the specific functions of HO-1 and HO-2 in skeletal muscle.
• To determine the impact of HO deficiency on muscle phenotype, mitochondrial function, and neuromuscular junctions.
• To evaluate the therapeutic efficacy of exogenous carbon monoxide (CO) in restoring muscle function in HO-deficient mice.

Main Methods:

• Generation and analysis of Hmox1/2 double-knockout mice alongside single knockouts and wild-type controls.
• Assessment of endurance capacity via treadmill running, muscle fiber-type distribution, neuromuscular junction morphology, and mitochondrial respiration.
• Analysis of neuronal firing dynamics and administration of inhaled CO to evaluate its rescue potential.

Main Results:

• HO-1 deficiency impaired oxidative fibers, mitochondrial respiration, and endurance.
• HO-2 deficiency was linked to neuromuscular junction remodeling and altered neuronal firing.
• Carbon monoxide (CO) treatment in double-knockout mice restored fiber type distribution, improved mitochondrial function, and significantly enhanced endurance, mimicking exercise adaptations.

Conclusions:

• HO-1 and HO-2 exhibit distinct roles in skeletal muscle adaptation and plasticity.
• HO-1 influences mitochondrial content and muscle plasticity, while HO-2 impacts neuromuscular plasticity and exercise responsiveness.
• Exogenous CO effectively rescues deficits in HO-deficient muscle, highlighting its therapeutic potential for conditions limiting exercise.