Abstract
Novel experimental methods, including a modified single fiber in vitro motility assay, X-ray diffraction experiments, and mass spectrometry analyses, have been performed to unravel the molecular events underlying the aging-related impairment in human skeletal muscle function at the motor protein level. The effects of old age on the function of specific myosin isoforms extracted from single human muscle fiber segments, demonstrated a significant slowing of motility speed (P < 0.001) in old age in both type I and IIa myosin heavy chain (MyHC) isoforms. The force-generating capacity of the type I and IIa MyHC isoforms was, on the other hand, not affected by old age. Similar effects were also observed when the myosin molecules extracted from muscle fibers were exposed to oxidative stress. X-ray diffraction experiments did not show any myofilament lattice spacing changes, but unraveled a more disordered filament organization in old age as shown by the greater widths of the 1, 0 equatorial reflections. Mass spectrometry (MS) analyses revealed eight age-specific myosin post-translational modifications (PTMs), in which two were located in the motor domain (carbonylation of Pro79 and Asn81) and six in the tail region (carbonylation of Asp900, Asp904, and Arg908; methylation of Glu1166; deamidation of Gln1164 and Asn1168). However, PTMs in the motor domain were only observed in the IIx MyHC isoform, suggesting PTMs in the rod region contributed to the observed disordering of myosin filaments and the slowing of motility speed. Hence, interventions that would specifically target these PTMs are warranted to reverse myosin dysfunction in old age.
Highlights
Falls are a major cause of morbidity and mortality in the growing population of elderly citizens, constituting the leading reason of unintentional injury deaths in individuals over the age of 79
All in vitro motility measurements have been restricted to muscle fibers expressing the type I and type IIa myosin heavy chain (MyHC) isoform and fulfilling the criteria for acceptance, due to the paucity of muscle fibers expressing the IIx MyHC isoform in both young and old subjects
Regarding the evaluation of myosin under the oxidative stress in vitro, a total of seven fibers were collected from one additional young male subject and myosin function was compared between one half exposed to oxidative stress and the other half of the fiber serving as control
Summary
Falls are a major cause of morbidity and mortality in the growing population of elderly citizens, constituting the leading reason of unintentional injury deaths in individuals over the age of 79. The source of falls and fall-related injuries in old age are complex and involve multiple risk factors. The difficulty in recovering from a threatening fall, which is impaired in old age, is not related to an impairment of the sensory process or to the motor planning that leads to the initiation of muscle contraction (Schultz et al, 1997). Understanding the aging muscle, the loss of speed and force in old age, appears primordial in deciphering potential ‘preventative’ or ‘therapeutic’ approaches
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