# Exercise Protects Skeletal Muscle Fibers from Age-Related Dysfunctional Remodeling of Mitochondrial Network and Sarcotubular System

## TL;DR

Regular exercise prevents age-related muscle decline by maintaining mitochondrial and calcium regulation structures in muscle fibers.

## Contribution

Exercise preserves mitochondrial positioning and sarcotubular system integrity, preventing age-related dysfunction.

## Key findings

- Mitochondrial positioning is lost in sedentary aging but preserved with exercise.
- SOCE function depends on regular muscle activity and is impaired by inactivity.
- Exercise rescues structural and functional impairments in muscle fibers caused by aging and inactivity.

## Abstract

What are the main findings?
Studying the effect of inactivity vs. exercise on ultrastructure of skeletal muscle fibers has given us the opportunity to discover that the correct position of mitochondria is lost in sedentary aging and inactivity, but is maintained by regular exercise.Function of SOCE (a mechanism that allows fibers to use external Ca2+ and limit muscle fatigue) also depends on regular muscle activity.

Studying the effect of inactivity vs. exercise on ultrastructure of skeletal muscle fibers has given us the opportunity to discover that the correct position of mitochondria is lost in sedentary aging and inactivity, but is maintained by regular exercise.

Function of SOCE (a mechanism that allows fibers to use external Ca2+ and limit muscle fatigue) also depends on regular muscle activity.

What are the implications of the main findings?
The maintenance of the internal architecture of muscle fibers is crucial for their capability to function properly.The proper position of mitochondria in proximity of sites of Ca2+ release and Ca2+ entry may be crucial for the metabolic efficiency of muscle, and thus of the entire organism.

The maintenance of the internal architecture of muscle fibers is crucial for their capability to function properly.

The proper position of mitochondria in proximity of sites of Ca2+ release and Ca2+ entry may be crucial for the metabolic efficiency of muscle, and thus of the entire organism.

In skeletal muscles fibers, cellular respiration, excitation–contraction (EC) coupling (the mechanism that translates action potentials in Ca2+ release), and store-operated Ca2+ entry (SOCE, a mechanism that allows recovery of external Ca2+ during fatigue) take place in organelles specifically dedicated to each function: (a) aerobic ATP production in mitochondria; (b) EC coupling in intracellular junctions formed by association between transverse tubules (TTs) and sarcoplasmic reticulum (SR) named triads; (c) SOCE in Ca2+ entry units (CEUs), SR-TT junctions that are in continuity with membranes of triads, but that contain a different molecular machinery (see Graphical Abstract). In the past 20 years, we have studied skeletal muscle fibers by collecting biopsies from humans and isolating muscles from animal models (mouse, rat, rabbit) under different conditions of muscle inactivity (sedentary aging, denervation, immobilization by casting) and after exercise, either after voluntary training in humans (running, biking, etc.) or in mice kept in wheel cages or after running protocols on a treadmill. In all these studies, we have assessed the ultrastructure of the mitochondrial network and of the sarcotubular system (i.e., SR plus TTs) by electron microscopy (EM) and then collected functional data correlating (i) the changes occurring with aging and inactivity with a loss-of-function, and (ii) the structural improvement/rescue after exercise with a gain-of-function. The picture that emerged from this long journey points to the importance of the internal architecture of muscle fibers for their capability to function properly. Indeed, we discovered how the intracellular organization of the mitochondrial network and of the membrane systems involved in controlling intracellular calcium concentration (i[Ca2+]) is finely controlled and remodeled by inactivity and exercise. In this manuscript, we give an integrated picture of changes caused by inactivity and exercise and how they may affect muscle function.