The Influence of Supplemental Dietary Linoleic Acid on Skeletal Muscle Contractile Function in a Rodent Model of Barth Syndrome

Abstract

Barth syndrome is a rare and incurable X-linked (male-specific) genetic disease that affects the protein tafazzin (Taz). Taz is an important enzyme responsible for synthesizing biologically relevant cardiolipin (for heart and skeletal muscle, cardiolipin rich in linoleic acid), a critical phospholipid of mitochondrial form and function. Mutations to Taz cause dysfunctional mitochondria, resulting in exercise intolerance due to skeletal muscle weakness. To date, there has been limited research on improving skeletal muscle function, with interventions focused on endurance and resistance exercise. Previous cell culture research has shown therapeutic potential for the addition of exogenous linoleic acid in improving Taz-deficient mitochondrial function but has not been examined in vivo. The purpose of this study was to examine the influence of supplemental dietary linoleic acid on skeletal muscle function in a rodent model of Barth syndrome, the inducible Taz knockdown (TazKD) mouse. One of the main findings was that TazKD soleus demonstrated an impaired contractile phenotype (slower force development and rates of relaxation) in vitro compared to their WT littermates. Interestingly, this impaired contractile phenotype seen in vitro did not translate to altered muscle function in vivo at the whole-body level. Also, supplemental linoleic acid attenuated, to some degree, in vitro impaired contractile phenotype in TazKD soleus, and these findings appear to be partially mediated by improvements in cardiolipin content and resulting mitochondrial supercomplex formation. Future research will further examine alternative mechanisms of dietary supplemental LA on improving skeletal muscle contractile dysfunction in TazKD mice.

Heterozygous SOD2 deletion selectively impairs SERCA function in the soleus of female mice

“…For example, SERCA Ca 2+ uptake was shown to be reduced by 25% in rat cardiomyocytes exposed to excessive ROS (Morris & Sulakhe, 1997). Additionally, we have shown that SERCA‐specific oxidative damage correlated with reduced maximal SERCA activity in taffazin‐deficient mice, a model of Barth syndrome (Braun et al, 2019), and recent work has also demonstrated slowed muscle relaxation time in the soleus muscles of these mice (Elkes et al, 2021). Together, these studies highlight the relationship between impaired SERCA function and increased T‐nitration.…”

Barth Syndrome Cardiomyopathy: An Update

“…Recently, Elkes et al isolated soleus muscle from Taz KD and control mice that were under dietary LA supplementation and performed ex vivo analysis for contractile function. The results revealed that LA supplementation ameliorated the soleus contractile function impairment in Taz KD mice [141]. Further in vivo analysis utilizing Taz KO mouse models is required for testing the therapeutic effects of LA supplementation and BEL, as well as determining their proper doses and potential side effects.…”

“…Increased incorporation of linoleoyl groups into nascent CL resulting in the production of mature CL without requiring the remodeling process [71,140,141].…”

Linoleic Acid‐Rich Oil Alters Circulating Cardiolipin Species and Fatty Acid Composition in Adults: A Randomized Controlled Trial

“…Dietary LA impacts mitochondrial respiration in muscles in preclinical rodent models of mitochondria dysfunction. [ 40,55 ] In a recent study, dietary LA partially restored LA 4 CL and muscle contractile force phenotype in skeletal muscle of mice deficient of tafazzin. [67] In rats with heart failure, the reduction of LA 4 CL and mitochondrial respiration was prevented when fed a diet with LA.…”