Elsevier

Experimental Gerontology

Volume 42, Issue 10, October 2007, Pages 931-938
Experimental Gerontology

Mini Review
Age-related decline in actomyosin structure and function

https://doi.org/10.1016/j.exger.2007.06.015Get rights and content

Abstract

This review focuses on the role of changes in the contractile proteins actin and myosin in age-related deterioration of skeletal muscle function. Functional and structural changes in contractile proteins have been determined indirectly from specific force and unloaded shortening velocity of permeabilized muscle fibers, and were detected directly from site-directed spectroscopy in muscle fibers and from biochemical analysis of purified actin and myosin. Contractile proteins from aged and young muscle differ in (a) myosin and actomyosin ATPase activities, (b) structural states of myosin in contracting muscle, (c) the state of oxidative modifications. The extent of age-related physiological and molecular changes is dependent on the studied animal, the animal’s age, and the type of muscle. Therefore, understanding the aging process requires systematic, multidisciplinary studies on physiological, biochemical, structural, and chemical changes in specific muscles.

Introduction

Aging is associated with a progressive loss of muscle mass, slowing of muscle movement, and decline in muscle strength. The mechanisms of age-related deterioration of contractility involve multiple factors associated with changes in the process of muscle excitation, regulation, and molecular interactions. This review is focused on age-related changes in the interaction between the contractile proteins actin and myosin.

Section snippets

Age-related changes in the contractility of permeabilized muscle

Physiological studies have detected age-related deterioration of muscle contractility in both intact and permeabilized muscle; the latter, which lacks the membrane-bound excitation–contraction coupling system and soluble proteins involved in energy metabolism, offers more direct information on contractile proteins. Studies on permeabilized muscle from several strains of rats (Fischer 344 Brown Norway F1 Hybrid, Wistar and Fischer 344) showed that the two principal contractile parameters,

Brief review of muscle structure and molecular basis of contractility

The basic contractile unit of muscle, the myofibril, consists of a linear array of sarcomeres, and each sarcomere contains interdigitating thick and thin filaments. The main components of the thick filament are myosin molecules aggregated vial their “tail” regions into a bipolar filament. The catalytic and force-generating function of myosin is located in its “head” region, which contains the catalytic domain (with sites for ATP hydrolysis and interaction with actin), and the light chain (LC)

Age-related changes in actomyosin ATPase activity

Measurements of muscle ATPase activity is often performed on myofibrils (minced muscle fibers), which preserve the organization and interaction between actin and myosin in the muscle, while their uniform suspension enables quantitative determination of the protein concentration and specific enzymatic (ATPase) activity. Numerous biochemical studies established that myofibrillar ATPase activity at high (0.6 M) salt concentration is quite sensitive to post-translational changes in myosin,

Age-related changes in the functional properties of myosin and actin: in vitro motility

The contractile properties of purified actin and myosin can be directly studied using the in vitro motility assay, a novel method for analyzing the interaction of actin and myosin at the single-molecule level. In this assay, isolated myosin molecules are immobilized on the glass surface, fluorescent actin filaments are added, and sliding movement of these filaments, initiated by addition of ATP, is directly observed under an optical microscope (Fig. 4).

The in vitro motility assay performed on

Age-related changes in muscle protein structure

Our laboratories initiated studies of the structural basis of age-related changes in muscle contractility by electron paramagnetic resonance (EPR). EPR is a high-resolution spectroscopic method which, in combination with site-specific spin labeling of Cys707 of myosin in permeabilized muscle fibers, detects changes in the structure of myosin associated with relaxation and isometric contraction of psoas muscle fibers (Ostap et al., 1995). In particular, this technique can be used to determine

Age-related oxidative modifications of actin and myosin

The hypothesis that age-related deterioration of muscle function involves oxidative modification of muscle proteins by reactive oxygen and nitrogen (ROS and NOS) species (Stadtman and Berlett, 1997) was suggested by a series of in vitro studies, showing that ROS and NOS such as peroxynitrite, hydroxyl radicals, H2O2, and nitric oxide inhibit force and induce changes in the Ca-sensitivity of intact and permeabilized muscle (Syrovy and Hodny, 1992, Andrade et al., 1998, Plant et al., 2000,

Age-related changes in the expression levels of actin and myosin

Skeletal muscle myosin is a hexamer composed of two heavy chains (MHC) containing regions involved in enzymatic and actin-binding functions of myosin, two regulatory light chains (MLC2) and two essential light chains (MLC1 and MLC3), which are implicated in calcium regulation of fiber V0 (Sweeney et al., 1988), the extent of actin-activated ATPase, and the speed of actin filament sliding in the in vitro motility assay (Wagner et al., 1979, Lowey et al., 1993, Timson, 2003). These properties of

Ca-regulation of interaction between actin and myosin in aging skeletal muscle

Ca-regulation of actin–myosin interaction in skeletal muscle occurs via troponin and tropomyosin, and one of the possible consequences of age-related changes in these proteins will be change in Ca-regulation of muscle contractility. This possibility was tested in the semimembranosus muscle of rat, but 30% age-related decrease in force was not accompanied by significant changes in its Ca-sensitivity (Lowe et al., 2002). On the other hand, proteomic studies on gastrocnemius and vastus lateralis

Summary and perspective

Physiological studies have detected age-related deterioration of contractility of permeabilized muscle fibers, dependent on the animal, age, and muscle. Structural analysis, using site-directed spin labeling, indicates directly that structural changes in myosin occur with aging. Biochemical and structural studies on myofibrils and isolated actin and myosin have reported age-related, muscle-specific molecular changes in myosin and actin, which are most likely due to oxidative modifications.

Acknowledgements

We thank Dawn Lowe, Deborah Ferrington, and Daniel Spakowicz for many useful discussions. This work was supported by NIH Grants to DDT (AR27906 and AG26160) and LT (AG17768 and AG21626).

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