Thyroid Hormone Stimulation of Autophagy Is Essential for Mitochondrial Biogenesis and Activity in Skeletal Muscle

Abstract

Thyroid hormone (TH) and autophagy share similar functions in regulating skeletal muscle growth, regeneration, and differentiation. Although TH recently has been shown to increase autophagy in liver, the regulation and role of autophagy by this hormone in skeletal muscle is not known. Here, using both in vitro and in vivo models, we demonstrated that TH induces autophagy in a dose- and time-dependent manner in skeletal muscle. TH induction of autophagy involved reactive oxygen species (ROS) stimulation of 5'adenosine monophosphate-activated protein kinase (AMPK)-Mammalian target of rapamycin (mTOR)-Unc-51-like kinase 1 (Ulk1) signaling. TH also increased mRNA and protein expression of key autophagy genes, microtubule-associated protein light chain 3 (LC3), Sequestosome 1 (p62), and Ulk1, as well as genes that modulated autophagy and Forkhead box O (FOXO) 1/3a. TH increased mitochondrial protein synthesis and number as well as basal mitochondrial O2 consumption, ATP turnover, and maximal respiratory capacity. Surprisingly, mitochondrial activity and biogenesis were blunted when autophagy was blocked in muscle cells by Autophagy-related gene (Atg)5 short hairpin RNA (shRNA). Induction of ROS and 5'adenosine monophosphate-activated protein kinase (AMPK) by TH played a significant role in the up-regulation of Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A), the key regulator of mitochondrial synthesis. In summary, our findings showed that TH-mediated autophagy was essential for stimulation of mitochondrial biogenesis and activity in skeletal muscle. Moreover, autophagy and mitochondrial biogenesis were coupled in skeletal muscle via TH induction of mitochondrial activity and ROS generation.

Changes in macroautophagy, chaperone-mediated autophagy, and mitochondrial metabolism in murine skeletal and cardiac muscle during aging

“…Thus, decreased Drp1 and PINK1 in the muscles from aged mice may lead to decreased mitochondrial fission and subsequent removal through autophagy. Substantial evidence also suggests that defective autophagy or mitophagy is associated with decreased PGC1α expression and mitochondrial biogenesis in a co-ordinate manner [23, 37]. In this connection, we found decreased PGC1α and COX IV mitochondrial protein levels in muscle from aged mice (Fig.…”

“…4A). PGC1α, a key factor for mitochondrial biogenesis [23], and mitochondrial protein COX IV also were decreased in muscle from aged mice (Fig. 4B), indicating that there was decreased mitochondrial biogenesis in muscle from aged mice.…”

Hepatic mitochondrial dysfunction is a feature of Glycogen Storage Disease Type Ia (GSDIa)

“…Since its transcription was not reduced, translational or post-translational effects are likely to be involved in the reduction of PGC1α levels. Additionally, our group recently showed that decreased autophagy is associated with decreased protein levels of PGC1α41, and since autophagy is decreased in GSDIa, it is possible that a similar mechanism may be involved here16.…”

Role of thyroid hormone in skeletal muscle physiology

“…Additionally, D2 activity is important to treadmill exercise-induced PGC1A stimulation and its downstream effects on mitochondrial function of the soleus and gastrocnemius muscles (Bocco et al 2016). Recently, Lesmana and coworkers demonstrated that TH-induced mitochondrial biogenesis and activity are dependent on T 3 -induced autophagy (Lesmana et al 2016). These TH effects on mitochondria were blocked in L6 myotubes lacking the autophagy-related gene 5 (Atg5) by short hairpin RNA (shRNA) lentivirus transformation (Lesmana et al 2016).…”

“…Recently, Lesmana and coworkers demonstrated that TH-induced mitochondrial biogenesis and activity are dependent on T 3 -induced autophagy (Lesmana et al 2016). These TH effects on mitochondria were blocked in L6 myotubes lacking the autophagy-related gene 5 (Atg5) by short hairpin RNA (shRNA) lentivirus transformation (Lesmana et al 2016).…”