Age-related slowing of myosin actin cross-bridge kinetics is sex specific and predicts decrements in whole skeletal muscle performance in humans

Abstract

We hypothesize that age-related skeletal muscle dysfunction and physical disability may be partially explained by alterations in the function of the myosin molecule. To test this hypothesis, skeletal muscle function at the whole muscle, single fiber, and molecular levels was measured in young (21-35 yr) and older (65-75 yr) male and female volunteers with similar physical activity levels. After adjusting for muscle size, older adults had similar knee extensor isometric torque values compared with young, but had lower isokinetic power, most notably in women. At the single-fiber and molecular levels, aging was associated with increased isometric tension, slowed myosin actin cross-bridge kinetics (longer myosin attachment times and reduced rates of myosin force production), greater myofilament lattice stiffness, and reduced phosphorylation of the fast myosin regulatory light chain; however, the age effect was driven primarily by women (i.e., age-by-sex interaction effects). In myosin heavy chain IIA fibers, single-fiber isometric tension and molecular level mechanical and kinetic indexes were correlated with whole muscle isokinetic power output. Collectively, considering that contractile dysfunction scales up through various anatomical levels, our results suggest a potential sex-specific molecular mechanism, reduced cross-bridge kinetics, contributes to the reduced physical capacity with aging in women. Thus these results support our hypothesis that age-related alterations in the myosin molecule contribute to skeletal muscle dysfunction and physical disability and indicate that this effect is stronger in women.

Skeletal muscle myofilament adaptations to aging, disease, and disuse and their effects on whole muscle performance in older adult humans

“…This age-related diminution in muscle contraction tends to affect dynamic more than isometric function (Lanza et al, 2003; Callahan and Kent-Braun, 2011; Miller et al, 2013), which suggests skeletal muscle properties are altered in a manner that maintains higher forces at slower speeds of movement. Identification of interventions to halt or reverse age-related alterations in skeletal muscle quantity and quality, therefore, can help to maintain physical function and independent living in older adults.…”

The myosin super-relaxed state is disrupted by estradiol deficiency

“…Estradiol has recently been implicated in the regulation of RLC phosphorylation and contractility of cardiomyocytes [19,20]. In human skeletal muscle, a proteomic study showed age-dependent reduction of RLC phosphorylation [21], and it was recently shown that RLC phosphorylation is affected in muscle fibers of old women but not old men, relative to young counterparts [22]. Phosphorylation of RLC is also enhanced by estradiol in rodent skeletal muscle [23].…”

Age, human performance, and physical employment standards

“…These reductions appear to be more pronounced in the lower extremities and are attributed to a combined decline in the number and size of skeletal muscle fibres (Marks 2002;Kenny et al 2008). The major contributor to age-related sarcopenia is the simultaneous neuromuscular alterations such that there is selective age-related denervation of motor units, particularly type II fibres (Callahan and Kent-Braun 2011;Miller et al 2013). As a result, there is a proportional shift towards type I muscle fibres and an increase in the size of the remaining motor units, which subsequently increases the activation threshold of the muscle and decreases the speed of contraction (Miller et al 2014).…”

“…On the other hand, concentric muscular strength, which is most relevant for many other workers, including firefighters and nurses, has been shown to decline by 8%-10% per decade (Vilela et al 2015), particularly in the lower extremities. These deteriorations are mainly due to an age-related shift from type II to type I muscle fibres along with marked sarcopenia and are associated with pronounced impairments in work ability and performance (Doherty 2001;Miller et al 2013). In addition, there is a ϳ10% increase in the prevalence of musculoskeletal disease in male workers between the ages of 50 and 54 years (Tuomi et al 1991).…”