Skeletal Muscle Pathophysiology: The Emerging Role of Spermine Oxidase and Spermidine

Abstract

Skeletal muscle comprises approximately 40% of the total body mass. Preserving muscle health and function is essential for the entire body in order to counteract chronic diseases such as type II diabetes, cardiovascular diseases, and cancer. Prolonged physical inactivity, particularly among the elderly, causes muscle atrophy, a pathological state with adverse outcomes such as poor quality of life, physical disability, and high mortality. In murine skeletal muscle C2C12 cells, increased expression of the spermine oxidase (SMOX) enzyme has been found during cell differentiation. Notably, SMOX overexpression increases muscle fiber size, while SMOX reduction was enough to induce muscle atrophy in multiple murine models. Of note, the SMOX reaction product spermidine appears to be involved in skeletal muscle atrophy/hypertrophy. It is effective in reactivating autophagy, ameliorating the myopathic defects of collagen VI-null mice. Moreover, spermidine treatment, if combined with exercise, can affect D-gal-induced aging-related skeletal muscle atrophy. This review hypothesizes a role for SMOX during skeletal muscle differentiation and outlines its role and that of spermidine in muscle atrophy. The identification of new molecular pathways involved in the maintenance of skeletal muscle health could be beneficial in developing novel therapeutic lead compounds to treat muscle atrophy.

Keywords: aging; atrophy; autophagy; oxidative stress; polyamines; skeletal muscle; spermidine; spermine oxidase; transgenic mouse.

Figure 1

Polyamine metabolism. Schematic representation of mammalian polyamine metabolism showing enzyme network and substrate interconversion pathways. ODC: ornithine decarboxylase; SSAT: spermidine/spermine N¹-acetyltransferase; PAOX: polyamine oxidase; SMOX: spermine oxidase; SPMS: spermine synthase; SPDS: spermidine synthase.

Figure 2

Schematic illustration of the skeletal muscle differentiation process. During myogenesis, Pax3 and Pax7 are activated in quiescent progenitors. Then, progenitor cells differentiate into proliferating muscle precursor cells (myoblasts) and Myf5, MyoD, and myogenin expression stimulates myoblasts to differentiate into myotubes. The terminal stage of differentiation is mediated by the activation of genes responsible for muscle fiber (myofiber) architecture and functionality such as MHCs. Pax: paired box; Myf5: myogenic factor 5; MyoD: myogenic factor 3; MRF4: myogenic regulatory factor 4; MHC: myosin heavy chain.

Figure 3

Hypothetical representation of SMOX regulation during myogenesis. During the early stage of muscle differentiation, p21 expression increases, leading to reduced SMOX expression. During the differentiation process, p21 declines in a time-dependent manner, allowing SMOX expression.

Figure 4

Enzymatic reaction catalyzed by SMOX. The physiological substrate spermine (Spm) is oxidized by the SMOX enzyme into spermidine (Spd) with the production of 3-aminopropanal and hydrogen peroxide.

Figure 5

Schematic representation of spermidine effects of on forkhead box (FOXO) activity. The effect of spermidine on the attenuation of age-related skeletal muscle atrophy and diseases, through regulating autophagy via 5′ AMP-activated protein kinase (AMPK)/Protein Kinase B (AKT)/E1A binding protein p300 (EP300)-FOXO signal pathways.

Figure 6

Total-Smox mouse line. (A) Scheme of the genetic construct of the Total-Smox mouse line upon recombination of the loxP sites by Cre recombinase. The β-actin/Cytomegalovirus (CMV) fusion promoter drives the ubiquitous expression of the SMOX gene and the lacZ reporter gene. IRES: internal ribosome entry site. (B) LacZ staining of Total-Smox embryo.