Geromella, M. S. | Search bioRxiv

bioRxiv2022

Tideglusib mitigates dystrophic pathology in skeletal muscle and restores diastolic function in young D2 mdx mice

Introductory paragraphDuchenne muscular dystrophy (DMD) is a severe X-linked muscle wasting disorder that affects 1 in 5,000 males worldwide1. It is caused by the absence of functional dystrophin, which compromises muscle integrity, leading to progressive muscle wasting and weakness2. Glucocorticoids are the standard of care for patients with DMD as they delay the loss of ambulation by an average of 3 years3; however, they are also associated with adverse effects such as insulin resistance and increased risk of type 2 diabetes4. Thus, alternative therapeutic options should be explored. Here, we show that treating the DBA/2J mdx mouse with the glycogen synthase kinase 3 (GSK3) inhibitor, tideglusib, improved skeletal muscle function and insulin sensitivity, while also attenuating the hypermetabolic phenotype previously observed in these mice5. Furthermore, treating mdx mice with the GSK3 inhibitor, lithium, augmented the benefits of voluntary wheel running on insulin sensitivity and skeletal muscle function despite running half of the total distance compared to control-treated mdx mice. This is important given that some patients with DMD may not be able to engage in adequate amounts of physical activity. Thus, GSK3 inhibition alone or in combination with exercise can enhance skeletal muscle function and insulin sensitivity in mdx mice.

physiology↗

bioRxiv2021

Characterizing SERCA function in murine skeletal muscles after 35-37 days of spaceflight

It is well established that microgravity exposure causes significant muscle weakness and atrophy via muscle unloading. On Earth, muscle unloading leads to a disproportionate loss in muscle force and size with the loss in muscle force occurring at a faster rate. Though the exact mechanisms are unknown, a role for Ca2+ dysregulation has been suggested. The sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA) pump actively brings cytosolic Ca2+ into the SR, eliciting muscle relaxation and maintaining low intracellular Ca2+ ([Ca2+]i). SERCA dysfunction contributes to elevations in [Ca2+]i, leading to cellular damage and thus may contribute to the muscle weakness and atrophy observed with spaceflight. Here, we investigated SERCA function, SERCA regulatory protein content (sarcolipin, phospholamban, and neuronatin), and reactive oxygen/nitrogen species (RONS) protein adduction in murine skeletal muscle after 35-37 days of spaceflight. In male and female soleus muscles, spaceflight led to drastic impairments in Ca2+ uptake despite significant increases in SERCA1a protein content. We attribute this impairment to an increase in RONS production and elevated total protein tyrosine (T) nitration and cysteine (S) nitrosylation. Contrarily, in the tibialis anterior (TA) we observed an enhancement in Ca2+ uptake, which we attribute to a shift towards a faster muscle fiber type (i.e., increased myosin heavy chain IIb and SERCA1a) without elevated total protein T-nitration and S-nitrosylation. Thus, spaceflight affects SERCA function differently between the soleus and TA. As the soleus is severely affected by spaceflight, future studies should determine whether improving SERCA function in this muscle can mitigate muscle atrophy and weakness.

physiology↗