High Level of Uncoupling Protein 1 Expression in Muscle of Transgenic Mice Selectively Affects Muscles at Rest and Decreases Their IIb Fiber Content

Abstract

The mitochondrial uncoupling protein of brown adipose tissue (UCP1) was expressed in skeletal muscle and heart of transgenic mice at levels comparable with the amount found in brown adipose tissue mitochondria. These transgenic mice have a lower body weight, and when related to body weight, food intake and energy expenditure are increased. A specific reduction of muscle mass was observed but varied according to the contractile activity of muscles. Heart and soleus muscle are unaffected, indicating that muscles undergoing regular contractions, and therefore with a continuous mitochondrial ATP production, are protected. In contrast, the gastrocnemius and plantaris muscles showed a severely reduced mass and a fast to slow shift in fiber types promoting mainly IIa and IIx fibers at the expense of fastest and glycolytic type IIb fibers. These observations are interpreted as a consequence of the strong potential dependence of the UCP1 protonophoric activity, which ensures a negligible proton leak at the membrane potential observed when mitochondrial ATP production is intense. Therefore UCP1 is not deleterious for an intense mitochondrial ATP production and this explains the tolerance of the heart to a high expression level of UCP1. In muscles at rest, where ATP production is low, the rise in membrane potential enhances UCP1 activity. The proton return through UCP1 mimics the effect of a sustained ATP production, permanently lowering mitochondrial membrane potential. This very likely constitutes the origin of the signal leading to the transition in fiber types at rest. Uncoupling protein 1 (UCP1)1 is expressed exclusively in brown adipose tissue (reviewed in Refs. 1 and 2). Its presence in brown fat mitochondria is responsible for heat production by the mitochondria in brown adipocytes. UCP1 allows return of protons into the matrix without ATP synthesis, and therefore dissipates the proton electrochemical gradient built up after proton pumping by the respiratory complexes. When this gradient reaches high values this makes proton pumping and thus substrate oxidation less easy and therefore slows down respiration. Activity of UCP1 prevents this rise of the proton gradient and therefore allows respiration to occur at a high rate, without phosphorylation of ADP into ATP, and therefore energy is instantaneously released as heat. The essential role of the UCP1 in thermogenesis is illustrated by the cold intolerance of mice whose ucp1 gene has been disrupted (3). Recently, two genes coding for proteins highly homologous to UCP1 have been described (reviewed in Refs. 4 -6). Although there are experimental evidence supporting the hypothesis of an uncoupling activity of these proteins (7,8), their physiological relevance is still incompletely resolved (9 -11). We intended to obtain transgenic mice overexpressing the UCP1 in skeletal muscles, with the aim of examining the effects of the presence of this uncoupling protein on the pattern of myosin expression and metabolic characteristics of locomotor muscles. Two other reports pub...

Skeletal muscle mitochondrial uncoupling prevents diabetes but not obesity in NZO mice, a model for polygenic diabesity

“…Data are mean ± SE. *p \ 0.05; **p \ 0.01; ***p \ 0.001 compared to wt which were set as 1 muscle energy metabolism evident by a fiber type switch toward oxidative type 1 fibers (Couplan et al 2002;Ost et al 2014). This was preserved also with increasing NZO genetic background which could possibly account for the decreased lean body mass to which muscle contributes to a great extent.…”

“…These are two key genes of the serine, onecarbon, glycine (SOG) pathway which is induced by SM mitochondrial stress (Ost et al 2015). UCP1 expression in SM has been shown to induce a fiber type switch from glycolytic type II fibers toward oxidative type I fibers (Couplan et al 2002;Ost et al 2014). In accordance, expression of myosin heavy polypeptide 7, cardiac muscle, beta (Myh7) encoding a myosin found in cardiac muscle and in type I skeletal muscle fibers was highly increased in increased in both F1 and N2-tg mice.…”

“…Ectopic expression of uncoupling protein 1 (UCP1) in skeletal muscle has been shown to result in a phenotype characterized by increased energy expenditure, reduced body weight, reduced fat mass, improved glucose tolerance, decreased muscle energy efficiency, and altered substrate oxidation (Couplan et al 2002;Klaus et al 2005;Li et al 2000). UCP1-tg mice express the murine UCP1 gene in striated skeletal muscle, driven by the human skeletal actin promoter (Klaus et al 2005).…”

Augmenting energy expenditure by mitochondrial uncoupling: a role of AMP-activated protein kinase

“…Ectopic expression of UCP1 in SM has been achieved by three independent groups, using different promoters in transgenic constructs (Li et al 2000;Couplan et al 2002;Klaus et al 2005). Several transgenic lines were generated and investigated (Li et al 2000;Couplan et al 2002).…”

“…Several transgenic lines were generated and investigated (Li et al 2000;Couplan et al 2002). Studies of these transgenic mice, all of them containing UCP1 cDNA, provide the unique opportunity to analyze the ''true'' effects of ectopic UCP1 in SM independent of mouse background strain, animal maintenance, or possible artifacts due to the insertion site of the transgene.…”