Effects of aging, exercise, and disease on force transfer in skeletal muscle

Abstract

The loss of muscle strength and increased injury rate in aging skeletal muscle has previously been attributed to loss of muscle protein (cross-sectional area) and/or decreased neural activation. However, it is becoming clear that force transfer within and between fibers plays a significant role in this process as well. Force transfer involves a secondary matrix of proteins that align and transmit the force produced by the thick and thin filaments along muscle fibers and out to the extracellular matrix. These specialized networks of cytoskeletal proteins aid in passing force through the muscle and also serve to protect individual fibers from injury. This review discusses the cytoskeleton proteins that have been identified as playing a role in muscle force transmission, both longitudinally and laterally, and where possible highlights how disease, aging, and exercise influence the expression and function of these proteins.

Keywords: aging; dystrophin-glycoprotein complex; force transmission; injury.

Fig. 1.

Process of longitudinal force transfer in skeletal muscle contractions to overcome an external load. Dysfunctional (A) or suboptimal performance (B) of proteins involved in longitudinal force transfer (represented by the length of the Z-line in red) leads to a reduction in force and the rate of force development. In both circumstances, the elastic component of the muscle, influenced by proteins such as titin, nebulin, and α-actinin, needs to be overcome for the force produced to shift the external load. C: when the system is working properly, the force produced within a sarcomere will be transferred rapidly to the external load.

Fig. 2.

Role of lateral force transmission in membrane stability and integrity. A: dystrophin-glycoprotein complex (DGC) and integrins act like rivets and ties that couple the intracellular matrix to the extracellular matrix (ECM) and prevent shear stress from damaging the sarcolemma. B: loss of these complexes in muscular dystrophies weakens the connection between the intracellular and extracellular matrices, rendering individual fibers more susceptible to damage from shear. Therefore, loss in lateral force transmission appears to lead toward sarcolemma damage and membrane disruption.

Fig. 3.

Schematic diagram of the various cytoskeleton proteins involved in lateral and longitudinal force transfer. The dystrophin-associated glycoprotein and integrin complexes are key components in lateral force transmission, enabling skeletal muscle to accommodate shear loads and protect the muscle from contraction-induced injury. Titin, nebulin, the MARP (muscle ankryin repeat proteins) family, and muscle LIM protein (MLP) are involved in longitudinal force transfer and are important in the rate of force development in the muscle. Desmin and α-actinin link the two modes of force transmission and therefore play a key role in both processes.