The connection between the dynamic remodeling of the mitochondrial network and the regulation of muscle mass

Abstract

The dynamic coordination of processes controlling the quality of the mitochondrial network is crucial to maintain the function of mitochondria in skeletal muscle. Changes of mitochondrial proteolytic system, dynamics (fusion/fission), and mitophagy induce pathways that affect muscle mass and performance. When muscle mass is lost, the risk of disease onset and premature death is dramatically increased. For instance, poor quality of muscles correlates with the onset progression of several age-related disorders such as diabetes, obesity, cancer, and aging sarcopenia. To date, there are no drug therapies to reverse muscle loss, and exercise remains the best approach to improve mitochondrial health and to slow atrophy in several diseases. This review will describe the principal mechanisms that control mitochondrial quality and the pathways that link mitochondrial dysfunction to muscle mass regulation.

Keywords: Atrophy; Autophagy; FGF21; Fission; Fusion; Mitochondria; Mitochondrial proteostasis; Mitophagy; Myokines; Skeletal muscle.

Fig. 1

Mitochondria quality control pathways. a The mitochondrial proteases LONP1, ClpP, OMA1, YME1L1, and PARL maintained mitochondrial proteostasis. PARL, OMA1, and YME1L1 process OPA1 protein, critical for mitochondrial fusion and cristae remodeling. PARL degrades PINK1, regulating mitophagy. b Mitochondrial fusion is mediated by MFN1/2 and OPA1 to produce an elongated mitochondrial network. c DRP1 and MFF are the major proteins involved in mitochondrial fission. Fragmented mitochondria with low ΔΨm are removed by mitophagy. d BNIP3 and NIX are mitophagy receptors that bind to LC3 to tether mitochondria to the autophagosome. PINK1 accumulates on of depolarized mitochondria surface, where it phosphorylates ubiquitinated OMM proteins and the Parkin UBL domain. Parkin will further promote the ubiquitination of the outer mitochondrial membrane proteins. Then, the ubiquitinated proteins can be recognized by the p62/SQSTM1 adaptor, to initiate mitophagy. e Mild mitochondrial damage activates the release of mitochondrial-derived vesicles (MDVs) containing mitochondrial components for their degradation in the lysosome

Fig. 2

Mitochondria-derived signaling pathways controlling muscle mass and whole-body homeostasis. a Increased fission or decreased fusion leads to dysfunctional fragmented organelles, which activate the energy sensor AMPK by increasing the AMP/ATP ratio, ROS production, and the inflammatory response. P-AMPK directly phosphorylates FoxO3 increasing its transcriptional activity and affecting muscle mass. ROS production causes endoplasmic reticulum (ER) stress and activation of unfolded protein response (UPR). UPR induces the ATF4-dependent upregulation of FGF21 secreted by the muscle that contributes to muscle loss, causes a systemic metabolic shift, and premature senescence. b Balanced mitochondrial fusion and fission are critical for muscle function and whole-body homeostasis. c A reduction of mitochondrial fusion results in the accumulation of elongated dysfunctional mitochondria resulting in mitophagy impairment, loss of ER tethering, ER stress, increased mitochondrial calcium overload, and decreased cytosolic calcium causing cell death, muscle loss, and weakness. Dashed lines indicate mechanisms that need more studies