Sudarshan Dayanidhi

Skeletal muscle comprises approximately 50% of individual body mass and plays vital roles in locomotion, heat production, and whole body metabolic homeostasis. This tissue exhibits a robust diurnal rhythm that is under control of the suprachiasmatic nucleus (SCN) region of the hypothalamus. The SCN acts as a “central” coordinator of circadian rhythms, while cell-autonomous “peripheral” clocks are located within almost all other tissues/organs in the body. Synchronization of the peripheral clocks in muscles (and other tissues) together with the central clock is crucial to ensure temporally coordinated physiology across all organ systems. By virtue of its mass, human skeletal muscle contains the largest collection of peripheral clocks, but within muscle resides a local stem cell population, satellite cells (SCs), which have their own functional molecular clock, independent of the numerous muscle clocks. Skeletal muscle has a daily turnover rate of 1%–2%, so the regenerative capacity of this tissue is important for whole body homeostasis/repair and depends on successful SC myogenic progression (i.e., proliferation, differentiation, and fusion). Emerging evidence suggests that SC-mediated muscle regeneration may, in part, be regulated by molecular clocks involved in SC-specific diurnal transcription. Here we provide insights on molecular clock regulation of muscle regeneration/repair and provide a novel perspective on the interplay between SC-specific molecular clocks, myogenic programs, and cell cycle kinetics that underpin myogenic progression.

Background Mitochondrial abnormalities exist in gastrocnemius muscle of people with peripheral artery disease (PAD). Whether abnormalities in mitochondrial biogenesis and autophagy are associated with greater ischemia or walking impairment in PAD is unknown. Methods and Results Protein markers of mitochondrial biogenesis and autophagy and the abundance of mitochondrial electron transport chain complexes were quantified in gastrocnemius muscle biopsies from people with and without PAD. Their 6‐minute walk distance and 4‐m gait speed were measured. Sixty‐seven participants (mean age 65.0 years [±6.8], 16 [23.9%] women, 48 [71.6%] Black) were enrolled, including 15 with moderate to severe PAD (ankle brachial index [ABI] <0.60), 29 with mild PAD (ABI 0.60–0.90), and 23 without PAD (ABI 1.00–1.40). Abundance of all electron transport chain complexes was significantly higher in participants with lower ABI (eg, complex I: 0.66, 0.45, 0.48 arbitrary units [AU], respectively, P trend=0.043). Lower ABI values were associated with a higher LC3A/B II‐to‐LC3A/B I (microtubule‐associated protein 1A/1B‐light chain 3) ratio (2.54, 2.31, 2.15 AU, respectively, P trend=0.017) and reduced abundance of the autophagy receptor p62 (0.71, 0.69, 0.80 AU, respectively, P trend=0.033). The abundance of each electron transport chain complex was positively and significantly associated with 6‐minute walk distance and 4‐m gait speed at usual and fast pace only among participants without PAD (eg, complex I: r =0.541, P =0.008; r =0.477, P =0.021; r =0.628, P =0.001, respectively). Conclusions These results suggest that accumulation of electron transport chain complexes in gastrocnemius muscle of people with PAD may be because of impaired mitophagy in the setting of ischemia. Findings are descriptive, and further study in larger sample sizes is needed.